Best Available Therapy With or Without Meropenem for Bloodstream Infections by Enterobacterales With High Level of Resistance to Carbapenems (ABOVE)

Open-label Randomized Clinical Trial Comparing Best Available Therapy With or Without Meropenem for Bloodstream Infections by Enterobacterales With Minimal Inhibitory Concentrations for Meropenem Above 32mg/L

Enterobacterales resistant to carbapenem are cause of severe concern in hospital-acquired infections since therapeutic options are limited. Recently approved drugs, such as bela-lactam/beta-lactamase inhibitor, have been the drug of choice. However, its use is limited in low- and middle-income countries. Thus, therapy of these infections mostly relies on polymyxins and other old drugs.

The role of adjuvant carbapenem therapy in combination with polymyxins, aminoglycosides and other drugs is under investigation. From a pharmacokinetic/pharmacodynamic (PK/PD), there is an elevated probability that high-dose, extended infusion administered meropenem reach the PK/PD target of 40% above the minimal inhibitory concentration (MIC) of the pathogen when the MIC is 32mg/L or lower (non-susceptible isolates have MICs of 4mg/L or higher). However, the MIC is not routinely determined in clinical laboratories. In addition, high-level (above 32mg/L) resistance to carbapenems have been reported in many studies.

This open-label, randomized clinical trial aim to assess if the addition of meropenem to the best available therapy can increase the number of days alive and free of hospitalization in patients with bloodstream infections by Enterobacterales with MIC of meropenem above 32mg/L.

Study Overview

• Status: Terminated
• Conditions: Bloodstream Infection; Carbapenem-Resistant Enterobacteriaceae Infection
• Intervention / Treatment: Drug: Meropenem

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90035-903
      • Hospital De Clinicas De Porto Alegre
    • Porto Alegre, RS, Brazil, 90619-900
      • Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sul

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:

• Primary or secondary bloodstream infections by any specie of the Enterobacterales family with minimum inhibitory concentration (MIC) for meropenem >32mg/L;
• Agreement of the assistant team with the inclusion of the patient in the study;
• Agreement by the patient or legal guardian to sign the informed consent form.

Exclusion Criteria:

• Known pregnancy;
• Patients belonging to the population deprived of their liberty;
• Known allergy to meropenem;
• Use of ceftazidime-avibactam (or any other new antimicrobial agent that become available in Brazil during the study period) for the treatment of the current infection;
• Infection by an Enterobacterales isolates without in vitro susceptibility to at least one antimicrobial drug;
• Bloodstream co-infection by another gram negative bacilli;
• Concomitant infection at any site by a pathogen which meropenem is indicated;
• Neutropenia (<1000 neutrophils cells/mm3)
• Death expected within 48 hours of eligibility assessment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Meropenem plus Best Available Therapy plus; Meropenem 2g every 8 hours combined with the best available therapy (BAT). BAT will be defined according to the susceptibility profile and decision of the assistant team before randomization and should include at least one of the antimicrobials that, usually, have in vitro activity against carbapenem-resistant Enterobacterales isolates.; Polymyxin B or colistimethate;; Amikacin or gentamicin;; Tigecycline;; Another antimicrobial with in vitro susceptibility. Doses will be defined by the assistant team.	Drug: Meropenem; Meropenem 2g every 8h for patients with glomerular filtration rate (GFR) equal or higher that 50 mL/min. Dose adjustment is recommended for patients with GFR < 50mL/min.
No Intervention: Best Available Therapy; The best available therapy will be defined according to the susceptibility profile and decision of the assistant team before randomization and should include at least one of the antimicrobials that, usually, have in vitro activity against carbapenem-resistant Enterobacterales isolates.; Polymyxin B or colistimethate;; Amikacin or gentamicin;; Tigecycline;; Another antimicrobial with in vitro susceptibility. Doses will be defined by the assistant team.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive and free of hospitalization	Number of days in which patients are alive and out of the hospital	60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall mortality	Death for any cause	14, 28 and 60 days after randomization
Antimicrobial-free days	Number of days in which patients are alive and without use of antimicrobial drugs	60 days after randomization
Relapse of infection	Presence of infection with isolation of the same bacteria between 14 and 60 days after randomization.	60 days after randomization
Clostridioides difficile infection	Incidence of Clostridioides difficile infection	60 days after randomization
Acute Kidney Injury	Incidence of Acute Kidney Injury, according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria	14 days after randomization
Meropenem-related adverse effects	Incidence of adverse effects related to meropenem, such as neurological toxicity and hypersensitivity reactions	14 days after randomization

Collaborators and Investigators

• Sponsor: Hospital de Clinicas de Porto Alegre
• Collaborators: Conselho Nacional de Desenvolvimento Científico e Tecnológico

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2021
• Primary Completion (Actual): March 7, 2022
• Study Completion (Actual): March 7, 2022

Study Registration Dates

• First Submitted: May 3, 2021
• First Submitted That Met QC Criteria: May 3, 2021
• First Posted (Actual): May 6, 2021

Study Record Updates

• Last Update Posted (Actual): August 3, 2022
• Last Update Submitted That Met QC Criteria: August 1, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: treatment; carbapenem; carbapenem resistance; carbapenemase; polymyxins
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Infections; Communicable Diseases; Enterobacteriaceae Infections; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem
• Other Study ID Numbers: 2019-0401

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