Ampicillin and Ceftriaxone for the Treatment of Enterococcus Faecalis Infective Endocarditis. (DOBLEI)

Efficacy and Safety of Ampicillin and Ceftriaxone Continuous Infusion Versus Standard Therapy for the Treatment of Enterococcus Faecalis Infective Endocarditis (DOβLEI Study)

Phase IV, open-label, randomized and multicenter clinical trial to prove that patients with Enterococcus faecalis infective endocarditis treated with an antibiotic treatment as a continuous infusion is non-inferior to the standard treatment, usually administered in hospitalized patients.

Study Overview

• Status: Recruiting
• Conditions: Endocarditis, Infective
• Intervention / Treatment: Drug: Ampicillin plus ceftriaxone in continuous infusion; Drug: Ampicillin plus ceftriaxone in intermittent infusion of 14 days, after which the treatment may be changed

Detailed Description

The aim of the study is to prove that the continuous infusion of antibiotic treatment for the patients with Enterococcus faecalis infective endocarditis is as effective and safe as the standard treatment. The continuous infusion modality of treatment is expected to provide numerous benefits for individual patients, global health, and for the National Health Care System by reducing to hospital stays from 4-6 weeks to approximately 2-3 weeks and hospital-driven complications.

The mortality, rate of serious adverse events, total number of days of antibiotic treatment and days of hospitalization, among others, are included as secondary objectives.

This is a pragmatic study as the number or visits performed for the study are similar to the normal clinical follow-up for this patients. Final contact and final visit for the study will be performed at 365 days after the 42 days of treatment.

• Study Type: Interventional
• Enrollment (Estimated): 284
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Clara M Rosso Fernández, MD-PhD; Phone Number: +34955013414; Email: claram.rosso.sspa@juntadeandalucia.es
• Study Contact Backup: Name: Laura Herrera Hidalgo, MD-PhD; Phone Number: +34955013414; Email: lauraherrerahidalgo@gmail.com

Study Locations

• Spain
  • Alava, Spain, 01009
    • Recruiting
    • Hospital Universitario de Alava
    • Contact: Juan Carlos Gainzarain, MD; Email: juancarlos.gainzarainarana@osakidetza.eus
  • Barakaldo, Spain, 48903
    • Active, not recruiting
    • Hospital Universitario de Cruces
  • Barcelona, Spain, 08035
    • Not yet recruiting
    • Hospital Universitario Vall d'Hebron
    • Contact: Nuria Fernández Hidalgo, MD; Email: nufernan@gmail.com
  • Barcelona, Spain, 08036
    • Not yet recruiting
    • Hospital Clínico de Barcelona
    • Contact: Guillermo Cuervo Requena, MD; Email: glcuervo@clinic.cat
  • Donostia, Spain, 20014
    • Active, not recruiting
    • Hospital Universitario DE Donostia
  • Granada, Spain, 18014
    • Active, not recruiting
    • Hospital Universitario Virgen de Las Nieves
  • La Laguna, Spain, 38320
    • Recruiting
    • Hospital Universitario de Canarias
    • Contact: Remedios Alemán, MD; Email: remealeman@hotmail.com
  • Logroño, Spain, 26006
    • Active, not recruiting
    • Hospital San Pedro
  • Madrid, Spain, 28046
    • Not yet recruiting
    • Hospital Universitario La Paz
    • Contact: Belén Loeches, MD; Email: bloeches@yahoo.es
  • Madrid, Spain, 28040
    • Not yet recruiting
    • Hospital Clinico San Carlos
    • Contact: Ana Muñoz Gómez, MD; Email: amg.sevilla@gmail.com
  • Madrid, Spain, 28007
    • Active, not recruiting
    • Hospital Universitario Gregorio Maranon
  • Madrid, Spain, 28222
    • Active, not recruiting
    • Hospital Universitario Puerta del Hierro
  • Málaga, Spain, 29010
    • Active, not recruiting
    • Hospital Universitario Virgen de la Victoria
  • Málaga, Spain, 29010
    • Active, not recruiting
    • Hospital Universitario Regional de Malaga
  • Santander, Spain, 39008
    • Recruiting
    • Hospital Universitario Marques de Valdecilla
    • Contact: MD
    • Contact: Mª Carmen Fariñas, MD; Email: mcarmen.farinas@scsalud.es
  • Sevilla, Spain, 41013
    • Recruiting
    • Hospital Universitario Virgen del Rocio
    • Contact: Cesar Aristides de Alarcon gonzalez, MD; Phone Number: +34 955 013414; Email: aa2406ge@yahoo.es
  • Sevilla, Spain, 41009
    • Active, not recruiting
    • Hospital Universitario Virgen Macarena
  • Terrassa, Spain, 08221
    • Active, not recruiting
    • Hospital Universitari MútuaTerrassa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients
• Possible or definitive diagnosis of infective endocarditis due to Enterococcus faecalis
• Signed informed consent of patients

Exclusion Criteria:

• Allergy to penicillins or cephalosporins
• Pregnancy and lactation
• Polymicrobial infection including microorganisms different to E. faecalis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Continuous intravenous antibiotic infusion; Ampicillin 12g/24h plus ceftriaxone 4g/12h continuous infusion. The duration of treatment will be 42 days.	Drug: Ampicillin plus ceftriaxone in continuous infusion; Continuous intravenous antibiotic infusion during 42 days for Infective Endocarditis; Other Names: Experimental regimen
Active Comparator: Standard treatment; Ampicillin 2g/4h plus ceftriaxone 2g/12h intermittent infusion for a minimum of 14 days. Starting on day 14 of treatment, if the patient is discharged from the hospital, the following treatments will be permitted: Intravenous treatment in TADE programs according to the following regimens:Ampicillin 2g/4h plus ceftriaxone 2g/12h as an intermittent infusionTeicoplanin 10-12mg/kg/24hDaptomycin 10-12mg/kg/24hDalbavancin: Initial dose: 2 doses of 1500mg every 2 weeks. Maintenance dose: 1500mg every 15days.Linezolid: 600mg/12hours; Oral treatment according to the following regimens:Amoxicillin 1 g/6h + Moxifloxacin 400mg/24h.Amoxicillin 1 g/6h + Linezolid 600 mg/12h.Amoxicillin 1 g/6h + Rifampin 600 mg/12h.Linezolid 600 mg/12h + Moxifloxacin 400mg/24h.Linezolid 600 mg/12h + Rifampin 600 mg/12h. The duration of treatment will be 42 days	Drug: Ampicillin plus ceftriaxone in intermittent infusion of 14 days, after which the treatment may be changed; Ampicillin plus ceftriaxone as an intermittent infusion for a minimum of 14 days. After, if the patient is discharged from the hospital, the following treatments, until the 42-day treatment period is completed: Intravenous treatment according to the following regimens:Ampicillin plus ceftriaxone as an intermittent infusion, teicoplanin, daptomycin, dalbavancin or linezolid.; Oral treatment according to the following regimens: amoxicillin plus moxifloxacin, amoxicillin plus linezolid, amoxicillin plus rifampin, linezolid plus moxifloxacin or linezolid plus rifampin.; Other Names: Control regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical failure	It is defined as follow: i) Confirmed recurrence of E. faecalis infective endocarditis, ii) all-cause mortality. A composite primary endpoint has been chosen to include both a very clinically relevant variable and a hard variable such as survival	One year after the end of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapeutic failure	Number of deaths	Up to 12 months after treatment administration
Cardiac surgeries	Number of unplanned cardiac surgeries	Up to 12 months after treatment administration
Readmissions	Number of unplanned readmissions	Up to 12 months after treatment administration
Antibiotic treatment days	Number of antibiotic treatment days	Up to 12 months after treatment administration
Outpatient Parenteral Antimicrobial Therapy	Number of Outpatient Parenteral Antimicrobial Therapy	Up to 12 months after treatment administration
Healthcare-associated infections	Number of healthcare-associated infections	Up to 12 months after treatment administration
Recurrence	Number of recurrence of Enterococcus faecalis infective endocarditis	Up to 12 months after treatment administration
Minimum free serum concentration	Minimum free serum concentration of antibiotics used	Day 14
Steady-state plasma concentration	Steady-state plasma concentration of antibiotics used	Day 14
Pharmacokinetic parameters	Volume of distribution, clearance, elimination constant of antibiotics used	Day 14
Minimum Inhibitory Concentration	Minimum Inhibitory Concentration of ampicillin induced by ceftriaxone in the strains responsible for recurrences and control strains	Day 14
Adverse events	Number of medication-related adverse events	From randomisation until 30 days after the last dose administration

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la gestión de la Investigación en Sevilla
• Collaborators: Spanish Clinical Research Network - SCReN
• Investigators: Principal Investigator: HUVR Cesar Arístides de Alarcón González, MD-PhD, Fundación para la Gestión de la Investigación en Salud de Sevilla

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2024
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: May 13, 2024
• First Submitted That Met QC Criteria: May 16, 2024
• First Posted (Actual): May 21, 2024

Study Record Updates

• Last Update Posted (Actual): July 25, 2025
• Last Update Submitted That Met QC Criteria: July 24, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Antibiotics; Enterococcus faecalis; Outpatient Care; Endocarditis, Infective; Outpatient Infusion Therapies
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Infections; Bacterial Infections; Bacterial Infections and Mycoses; Cardiovascular Infections; Endocarditis; Endocarditis, Bacterial; Third Generation Cephalosporins; Beta Lactam Antibiotics; Anti-Bacterial Agents; Anti-Infective Agents; Ceftriaxone; Ampicillin
• Other Study ID Numbers: DOBLEI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The results will be shared with the investigators involved in the study, and will be shared when the analysis of the results is performed.
• IPD Sharing Time Frame: 6 months
• IPD Sharing Access Criteria: Direct collaborators within the study
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No