Bolus Versus Continuous Infusion of Meropenem (MERCY)

Continuous Infusion Versus Intermittent Administration of Meropenem in Critically Ill Patients: A Multicenter Randomized Double Blind Trial

This study arises from the need to optimize antibacterial drug usage to face increasing drug resistance among gram-negative pathogens in intensive care units. Gram-negative organisms are responsible for 70% of drug-resistant infections acquired in the intensive care unit. Meropenem is a β-lactam, carbapenem, antibacterial agent usually administered by intermittent infusion. As β-lactam efficacy is determined by the time in which the drug concentration exceeds the minimum inhibiting concentration of the target pathogen, intermittent infusion of this short half-lived drug can lead to precipitous drops in serum drug levels, an occurrence linked to emergence of resistant pathogens. The investigators hypothesize a beneficial effect of a continuous meropenem infusion on mortality and emergence of drug resistant pathogens. All patients enrolled will receive 1 g of meropenem bolus. After that, subjects will be randomized to receive a continuous infusion of study drug 3g/day or a bolus administration of the same amount of drugs. The investigators expect a reduction of mortality and emergence of extensive or pan drug resistant pathogens from 52 to 40% in the continuous infusion group.

Study Overview

• Status: Completed
• Conditions: Critical Illness; Antibiotic Resistant Infection
• Intervention / Treatment: Drug: Meropenem

• Study Type: Interventional
• Enrollment (Actual): 607
• Phase: Phase 4

Contacts and Locations

Study Locations

• Croatia
  • Dubrava, Croatia
    • University Hospital Dubrava
• Italy
  • Alba, Italy
    • Ospedale San Lazzaro ASL CN2
  • Campobasso, Italy
    • Ospedale A. cardarelli
  • Caserta, Italy
    • P.O. Pineta Grande - Castelvolturno
  • Firenze, Italy
    • Azienda Ospedaliero Universitaria Careggi - Firenze
  • Foggia, Italy
    • Azienda Universitario-Ospedaliera O.O.R.R.
  • Genova, Italy
    • E. O. Ospedali Galliera
  • Merano, Italy
    • Ospedale di Merano
  • Napoli, Italy
    • Università degli Studi della Campania "L. Vanvitelli
  • Padova, Italy
    • Azienda Ospedale - Università Padova - Ospedale "Sant'Antonio
  • Pisa, Italy
    • AOU Pisana
  • Potenza, Italy
    • A.O.R San Carlo
  • Reggio Calabria, Italy
    • Grande Ospedale Metropolitano
  • Rozzano, Italy
    • Humanitas Research Hospital
  • Torino, Italy
    • AO Città della Salute e della Scienza
  • Udine, Italy
    • Università di Udine
  • Cemona
    • Cremona, Cemona, Italy
      • ASST Cremona
  • Lazio
    • Roma, Lazio, Italy
      • Policlinico Univeristario Campus Bio-Medico
  • MI
    • Milan, MI, Italy, 20132
      • Ospedale San Raffaele di Milano
  • Puglia
    • Lecce, Puglia, Italy
      • Città di Lecce Hospital
  • Reggio Calabria
    • Catanzaro, Reggio Calabria, Italy
      • A.O.U. Mater Domini
  • Sardegna
    • Cagliari, Sardegna, Italy
      • Azienda Ospedaliera Universitaria
  • Venezia
    • San Dona' Di Piave, Venezia, Italy
      • USSL 10 Veneto
• Kazakhstan
  • Kazakhstan, Kazakhstan
    • Astana Medical University
• Russian Federation
  • Moscow, Russian Federation
    • I.M. Sechenov Firts Moscow State Medical
  • Moscow, Russian Federation
    • Federal Clinical & Research Center for Reanimatology and Rehabilitation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Will be enrolled patients who:

• Are able to express informed consent or the latter can be given by his/her next of kin or as requested by Ethical Committee.
• Need a new antibiotic treatment, by clinical judgment, with meropenem
• Are admitted to ICU
• Have Sepsis or septic shock. Sepsis defined as having all the following 1. SIRS (Systemic Inflammatory Response Syndrome); 2. suspected or documented infection; 3. a SOFA score ≥ 2. Septic shock defined as having all the following 1.Sepsis; 2. Persisting hypotension requiring vasopressors to maintain MAP ≥65mmHg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation.

Exclusion Criteria:

Will be excluded patients who:

• Are able to express informed consent and deny it
• Are already receiving study drug or other carbapenem both as a bolus or continuous infusion
• Have a known allergy or intolerance to study drug, to other carbapenem antibacterial agents or severe allergic reaction to β-lactam antibacterial agents or to anhydrous sodium carbonate (study drug excipient)
• Have a little chance of survival, as defined by a SAPS II score greater than 65
• Have concomitant acquired immunodeficiency syndrome (stage 3 according to CDC)
• Received immunosuppressant or long-term corticosteroid therapy (more than 0.5 mg/kg/day for over 30 days)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continuous infusion; Patient randomized to continuous infusion group, will receive a continuous infusion of meropenem according to their renal function (creatinine clearance -ClCr- estimated by Cockcroft-Gault formula and study day; for ClCr > 50 ml/min: 3 g / day, prepared as follows: 10 mg/ml of meropenem in NaCl 0.9% at 12,5 ml/h.; for ClCr < 50 ml/min: 2 g / day, prepared as follows: 10 mg/ml of meropenem in NaCl 0.9% at 8,3 ml/h. This solution will be replaced every time its duration exceeds the stability in use stated by the producer	Drug: Meropenem; Meropenem or injection vials to be re-constituted in a solution of NaCl 0.9%.
Active Comparator: Bolus; Patient randomized to bolus group, will receive a bolus infusion of meropenem according to their renal function (creatinine clearance -ClCr- estimated by Cockcroft-Gault formula): for Cl-Cr > 50 ml/min 1 g every 6 hours on first 24 hours, every 8 hours after; for Cl-Cr < 50 ml/min 1 g every 8 hours on first 24 hours, every 12 hours after	Drug: Meropenem; Meropenem or injection vials to be re-constituted in a solution of NaCl 0.9%.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or Emergence of new resistant bacteria	composite outcome: death from any cause at day 28; emergence of new XDR (extended drug resistant) or PDR (pan drug resistant) bacteria at day 28	day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death from any cause	Death from any cause	day 90
Antibiotic-free days	Proportion of days from randomization to day 28 or death in which subject didn't receive any antibiotics (excluding anti-fungal anti-viral drugs)	up to day 28 or death
ICU - free days	Number of days from randomization to day 28 (or death) in which the subject is outside the ICU. For any discharge lasting less than 48h, no ICU-free day will be computed. Re-admission lasting less than 24 hours will not reduce ICU-free days. Patients that will not survive outside ICU for at least 48 hours, will have a ICU-free day of zero	day 28 or death
Cumulative SOFA-free point	SOFA score will be evaluated every day up to day 28. SOFA-free daily score is 24 (maximum SOFA) minus actual SOFA. Cumulative SOFA-free is the sum of SOFA-free daily from randomization to date 28. Patients dead before day 28 can't ameliorate their SOFA-free score. This way, the higher the cumulative SOFA-free, the higher is the amelioration of the patient and his probability of survival.	up to day 28

Collaborators and Investigators

• Sponsor: Università Vita-Salute San Raffaele
• Investigators: Principal Investigator: Alberto Zangrillo, Prof, IRCCS San Raffaele Scientific Institute; Study Chair: Giacomo Monti, MD, IRCCS San Raffaele Scientific Institute

Publications and helpful links

General Publications

• Monti G, Galbiati C, Toffoletto F, Calabro MG, Colombo S, Ferrara B, Giardina G, Lembo R, Marzaroli M, Moizo E, Mucci M, Pasculli N, Plumari VP, Scandroglio AM, Tozzi M, Momesso E, Boffa N, Lobreglio R, Montrucchio G, Guarracino F, Benedetto U, Biondi-Zoccai G, D'Ascenzo F, D'Andrea N, Paternoster G, Ananiadou S, Ballestra M, De Sio A, Pota V, Cotoia A, Della Selva A, Bruni A, Iapichino G, Bradic N, Corradi F, Gemma M, Nogtev P, Petrova M, Agro FE, Cabrini L, Forfori F, Likhvantsev V, Bove T, Finco G, Landoni G, Zangrillo A; Collaborators. Continuous infusion versus intermittent administration of meropenem in critically ill patients (MERCY): A multicenter randomized double-blind trial. Rationale and design. Contemp Clin Trials. 2021 May;104:106346. doi: 10.1016/j.cct.2021.106346. Epub 2021 Mar 6.

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2018
• Primary Completion (Actual): October 1, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: February 26, 2018
• First Submitted That Met QC Criteria: March 1, 2018
• First Posted (Actual): March 2, 2018

Study Record Updates

• Last Update Posted (Actual): December 27, 2022
• Last Update Submitted That Met QC Criteria: December 23, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: meropenem; mortality; antibiotic resistance; critical illness; β-lactams; continuous antibacterial drug infusion
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem
• Other Study ID Numbers: MERCY/9A/OSR; 2016-002052-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No