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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Carbapenem-Resistant Enterobacteriaceae Infection, Bloodstream Infection

Intervention / Treatment
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* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Meropenem plus Best Available Therapy plus<br>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<br>* 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.<br>|
| No Intervention: Best Available Therapy<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carbapenem, carbapenemase, polymyxins, treatment, carbapenem resistance