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

Hospital de Clinicas de Porto Alegre

Status and phase: Terminated; Phase 3; Phase 2

Conditions: Bloodstream Infection; Carbapenem-Resistant Enterobacteriaceae Infection

Treatments: Drug: Meropenem

Study type: Interventional

Funder types: Other

Identifiers

NCT04876430

2019-0401

Details and patient eligibility

About

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.

Enrollment: 13 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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13 participants in 2 patient groups

Meropenem plus Best Available Therapy plus

Experimental group

Description:

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.

Treatment:

Drug: Meropenem

Best Available Therapy

No Intervention group

Description:

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.