Short vs Long of Usual Treatment for Non Complicated Enterococcal Bacteremia (INTENSE)

Fundación Pública Andaluza para la gestión de la Investigación en Sevilla

Status and phase: Enrolling; Phase 4

Conditions: Enterococcal Bacteremia

Treatments: Drug: Short-treatment of any active antibiotic regimen 7 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.; Drug: Long-treatment of any active antibiotic regimen 14 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT05394298

2021-003891-15 (EudraCT Number)

RCT- INTENSE

Details and patient eligibility

About

Randomized clinical trial to determine the optimal duration of antibiotic treatment for E. Faecalis or E. faecium bacteraemia, following an innovative DOOR / RADAR (Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR)) analysis methodology.

Phase IV clinical trial, open-labelled, randomized, pragmatic, multicenter study to demonstrate non-inferiority of a 7-day antibiotic regimen vs. 14 days in the treatment of bacteremia due to E. faecalis or E. faecium.

Full description

Phase IV clinical trial, open-labelled, randomized, pragmatic, multicenter study to demonstrate non-inferiority of a 7-day antibiotic regimen vs. 14 days in the treatment of bacteremia due to E. faecalis or E. faecium.

Adequate antibiotic regimen is included in the protocol; initially this regimen included ciprofloxacine but this has been modified si that in the last version 3 dated feb 6th ciprofloxacine is not allowed as a possible treatment for these patients.

Antibiotic regimen included as possible treatments in the study are the follows:

• Isolated strains sensitive to ampicillin: ampicillin 2g/6 or 8h (i.v)
• Strains resistant to ampicillin and/or patients with allergy to beta-lactam drugs:
• Vancomycin: 15 mg/kg/12h i.v (with determination of trough plasma levels on day 2-3 of treatment if available).
• Linezolid: 600 mg/12 hours (i.v)
• Daptomycin: 8-10 mg/kg/day (i.v).

Intra-abdominal or soft tissue infections meeting study criteria, for which a polymicrobial infection is suspected:

Amoxicillin/clavulanic acid (isolates sensitive to ampicillin) 1 g/8h iv - Piperacillin/tazobactam (isolates sensitive to ampicillin) 4 g/8h (i.v.) - Combination of vancomycin, linezolid or daptomycin with a drug active against Gram-negative and anaerobic bacteria to ensure complete coverage in the case of bacteremia with a presumably polymicrobial focus.

Oral Treatment: In order to facilitate discharge of patients in both arms and reduce the risk of complications, as well as in keeping with the increasing use of this practice, the option to switch to oral therapy is allowed at the discretion of the responsible clinician, in both arms in patients with hemodynamic stability who tolerate oral treatment, at the discretion of the physician.

responsable.

• Amoxicillin 1g/8h or amoxicillin/clavulanic acid 875/125mg/8h if polymicrobial infection is suspected Linezolid 600mg/12h The choice will be in this order, according to the sensitivity of the isolate and allergies or other common circumstances for the use of these drugs.

The previous version allowed the use of cipro at the discretion of the clinicians as a sequential treatment option based on the fact that it is a clinical trial for low-risk bacteraemias in order to facilitate early sequential treatment (and thus avoid unnecessarily prolonging the hospital admissions.We decided to withdraw it on the basis that currently the EUCAST breakpoints only apply to urinary tract infections.The direct consequence is that the number of sequential treatment options is reduced.

Enrollment: 284 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Adult patients (18 years of age or older) hospitalised with monomicrobial E. faecalis or E. faecium bacteremia.
• Negative follow-up blood cultures performed between days 2 and 3 of active treatment.
• Disappearance of fever (>37.8ºC) within the first 72 hours.
• Signed informed consent.

The previous version allowed this inclusion criterion "Early adequate control of the source of bacteremia within 72 hours in the cases in which it is feasible and necessary (urinary or biliary tract release; abscess drainage; catheter-removal, etc)", which is now removed because it is already an exclusion criterion.

Exclusion criteria

• patients with polymicrobial bacteremia
• Patients with limited life expectancy in whom only conservative clinical management had been decided.
• Hemodynamic instability on day 5-6 after the start of active treatment.
• Patients wearing endovascular devices or prosthetic heart valves.
• Source of uncontrolled bacteremia adequately defined as undrained abscess, bile duct infection associated with plastic prostheses not removed or not replaced within the first 72 hours of bacteraemia, other infections related to non-removed prostheses, prostatitis, and infective endocarditis, as well as infections that require prolonged treatment, such as joint and bone infections.
• Existence of a secondary focus, different from the initial one, or presence of metastatic focus of infection.
• Severe neutropenia (<500 cells / mm3) at the time of bacteremia diagnosis.
• Pregnancy and lactation.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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284 participants in 2 patient groups

Short-treatment of any active antibiotic regimen

Experimental group

Description:

7 days from the initiation of an appropriate antimicrobial therapy and documented resolution of bacteremia (negative control blood cultures performed on day 2 or 3)

Treatment:

Drug: Short-treatment of any active antibiotic regimen 7 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.

Long-treatment of any active antibiotic regimen

Active Comparator group

Description:

14 days of any active antibiotic treatment from the date of the last positive blood culture and documented resolution of bacteremia (negative control blood cultures performed on day 2 or 3)

Treatment:

Drug: Long-treatment of any active antibiotic regimen 14 days of any active antibiotic treatment for uncomplicated enterococcal bacteremia.