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

NCT04876430 | Terminated Phase 2 DMC

• 1 other identifier: 2019-0401
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Carbapenem-Resistant Enterobacteriaceae Infection; Bloodstream Infection

Keywords

carbapenem; carbapenemase; polymyxins; treatment; carbapenem resistance

Outcome Measures

Primary Outcomes (1)

• Days alive and free of hospitalization

  Number of days in which patients are alive and out of the hospital

  60 days

Secondary Outcomes (6)

• Overall mortality

  14, 28 and 60 days after randomization

• Antimicrobial-free days

  60 days after randomization

• Relapse of infection

  60 days after randomization

• Clostridioides difficile infection

  60 days after randomization

• Acute Kidney Injury

  14 days after randomization

Study Arms (2)

Meropenem plus Best Available Therapy plus

EXPERIMENTAL

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. 1. Polymyxin B or colistimethate; 2. Amikacin or gentamicin; 3. Tigecycline; 4. Another antimicrobial with in vitro susceptibility. Doses will be defined by the assistant team.

Drug: Meropenem

Best Available Therapy

NO INTERVENTION

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. 1. Polymyxin B or colistimethate; 2. Amikacin or gentamicin; 3. Tigecycline; 4. Another antimicrobial with in vitro susceptibility. Doses will be defined by the assistant team.

Interventions

Meropenem DRUG

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.

Meropenem plus Best Available Therapy plus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hospital de Clinicas de Porto Alegre: lead
• Conselho Nacional de Desenvolvimento Científico e Tecnológico: collaborator

Study Sites (2)

Hospital de Clínicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, 90035-903, Brazil

Location

Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul

Porto Alegre, Rio Grande do Sul, 90619-900, Brazil

Location

MeSH Terms

Conditions

Sepsis

Interventions

Meropenem

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 3, 2021
• First Posted: May 6, 2021
• Study Start: May 4, 2021
• Primary Completion: March 7, 2022
• Study Completion: March 7, 2022
• Last Updated: August 3, 2022

Record last verified: 2022-08

Locations

BR (2)