Clinical trial NCT03452839: Bolus Versus Continuous Infusion of Meropenem
Official title: Continuous Infusion Versus Intermittent Administration of Meropenem in Critically Ill Patients: A Multicenter Randomized Double Blind Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Antibiotic Resistant Infection
Critical Illness
Keywords: meropenem
antibiotic resistance
critical illness
β-lactams
continuous antibacterial drug infusion
mortality
Lead sponsor: Università Vita-Salute San Raffaele
Sponsor class: OTHER
First posted: 2018-03-02
Enrollment: 607
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Death or Emergence of new resistant bacteria
timeFrame: day 28
Secondary outcomes:
measure: Death from any cause
timeFrame: day 90
measure: Antibiotic-free days
timeFrame: up to day 28 or death
measure: ICU - free days
timeFrame: day 28 or death
measure: Cumulative SOFA-free point
timeFrame: up to day 28
Other outcomes:
Locations:
city: Dubrava
country: Croatia
facility: University Hospital Dubrava
city: Cremona
country: Italy
facility: ASST Cremona
state: Cemona
city: Roma
country: Italy
facility: Policlinico Univeristario Campus Bio-Medico
state: Lazio
city: Milan
country: Italy
facility: Ospedale San Raffaele di Milano
state: MI
city: Lecce
country: Italy
facility: Città di Lecce Hospital
state: Puglia
city: Catanzaro
country: Italy
facility: A.O.U. Mater Domini
state: Reggio Calabria
city: Cagliari
country: Italy
facility: Azienda Ospedaliera Universitaria
state: Sardegna
city: San Dona' Di Piave
country: Italy
facility: USSL 10 Veneto
state: Venezia
city: Alba
country: Italy
facility: Ospedale San Lazzaro ASL CN2
city: Campobasso
country: Italy
facility: Ospedale A. Cardarelli
city: Caserta
country: Italy
facility: P.O. Pineta Grande - Castelvolturno
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi - Firenze
city: Foggia
country: Italy
facility: Azienda Universitario-Ospedaliera O.O.R.R.
city: Genova
country: Italy
facility: E. O. Ospedali Galliera
city: Merano
country: Italy
facility: Ospedale di Merano
city: Napoli
country: Italy
facility: Università degli Studi della Campania "L. Vanvitelli
city: Padova
country: Italy
facility: Azienda Ospedale - Università Padova - Ospedale "Sant'Antonio
city: Pisa
country: Italy
facility: AOU Pisana
city: Potenza
country: Italy
facility: A.O.R San Carlo
city: Reggio Calabria
country: Italy
facility: Grande Ospedale Metropolitano
city: Rozzano
country: Italy
facility: Humanitas Research Hospital
city: Torino
country: Italy
facility: AO Città della Salute e della Scienza
city: Udine
country: Italy
facility: Università di Udine
city: Kazakhstan
country: Kazakhstan
facility: Astana Medical University
city: Moscow
country: Russian Federation
facility: Federal Clinical & Research Center for Reanimatology and Rehabilitation
city: Moscow
country: Russian Federation
facility: I.M. Sechenov Firts Moscow State Medical
Study officials:
affiliation: IRCCS San Raffaele Scientific Institute
name: Alberto Zangrillo, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS San Raffaele Scientific Institute
name: Giacomo Monti, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: Monti G, Bradic N, Marzaroli M, Konkayev A, Fominskiy E, Kotani Y, Likhvantsev VV, Momesso E, Nogtev P, Lobreglio R, Redkin I, Toffoletto F, Bruni A, Baiardo Redaelli M, D'Andrea N, Paternoster G, Scandroglio AM, Gallicchio F, Ballestra M, Calabro MG, 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, Agro FE, Bove T, Corradi F, Forfori F, Longhini F, Cecconi M, Landoni G, Bellomo R, Zangrillo A; MERCY Investigators. Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial. JAMA. 2023 Jul 11;330(2):141-151. doi: 10.1001/jama.2023.10598.