Clinical trial NCT04876430: Best Available Therapy With or Without Meropenem for Bloodstream Infections by Enterobacterales With High Level of Resistance to Carbapenems
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Carbapenem-Resistant Enterobacteriaceae Infection
Bloodstream Infection
Keywords: carbapenem
carbapenemase
polymyxins
treatment
carbapenem resistance
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Conselho Nacional de Desenvolvimento Científico e Tecnológico
First posted: 2021-05-06
Enrollment: 13
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: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Days alive and free of hospitalization
timeFrame: 60 days
Secondary outcomes:
measure: Overall mortality
timeFrame: 14, 28 and 60 days after randomization
measure: Antimicrobial-free days
timeFrame: 60 days after randomization
measure: Relapse of infection
timeFrame: 60 days after randomization
measure: Clostridioides difficile infection
timeFrame: 60 days after randomization
measure: Acute Kidney Injury
timeFrame: 14 days after randomization
measure: Meropenem-related adverse effects
timeFrame: 14 days after randomization
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul
state: RS
Study officials:
References: