Beta-Lactam Antibiotics InitiaL ExpoSure OptimisEd in CriticallY Ill Patients with SEpsis (BULLSEYE)

The aim of this study is to investigate if an initial short double dose of beta-lactam antibiotics will reduce mortality in critically ill patients with sepsis.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock; Sepsis - to Reduce Mortality in the Intensive Care Unit
• Intervention / Treatment: Drug: Double dosing of beta-lactam antibiotic

Detailed Description

Objective

To determine if using higher dosages of beta-lactam antibiotics in the initial phase of sepsis improves clinical outcome of critically ill patients.

Main trial endpoints

The main trial endpoint is all cause 28-day mortality.

Secondary trial endpoints

Secondary trial endpoints include: Hospital length of stay, ICU length of stay, microbiological eradication, time to shock reversal, clinical cure, Δ Lactate, Δ PCT, Δ SOFA, 90- day mortality, 365-day mortality, pharmacodynamic target, post study calculation of the costs in both study, groups, EQ5D questionnaire 3 and 12 months after Admission, iMTA productivity questionnaire 3 and 12 months after admission, iMTA medical consumption questionnaire 3 and 12 months after admission and the number of adverse events.

Trial design

This is an open label, randomized controlled trial.

Trial population

The trial population will consist of adult patients admitted to the intensive care department with sepsis who will be treated according to protocol with beta-lactam antibiotics.

Interventions

During the trial participants in the intervention group will receive a double dose of antibiotics for the first 48 hours in comparison to the standard dose in the control group.

• Study Type: Interventional
• Enrollment (Estimated): 980
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Birgit C.P. Koch, PharmD; Phone Number: 0031107033202; Email: b.koch@erasmusmc.nl

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Recruiting
    • Maasstad Ziekenhuis
    • Contact: Dr. Den Uil; Phone Number: 0031102913474; Email: uilc@maasstadziekenhuis.nl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• ≥18 years of age
• Receiving intravenous antibiotic therapy of the target drugs (including continuous infusion of beta-lactam antibiotics)
• Primary infection
• Admitted to the ICU
• Meeting the Sepsis-3 criteria for septic shock: sepsis in addition to shock requiring the start of vasopressors to maintain a mean arterial pressure 65 mmHg or greater, and a serum lac tate level greater than 2.0 mmol/L following "adequate fluid resuscitation".

Exclusion Criteria:

• Patient or legal representative not available to give informed consent within 72 hours after admittance
• Pregnancy
• Admittance for burn wounds
• Patients receiving target antibiotics only as prophylaxis within the context of Selective Diges tive tract Decontamination (SDD)
• Enrolment in another interventional trial
• Patient received the study antibiotic for more than 24 hours before inclusion
• Patient receiving extracorporeal membrane oxygenation (ECMO)
• Patient is already treated with a double dose of antibiotics based on suspected infection

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
No Intervention: Control; This arm will receive standard of care according to local protocol.
Experimental: Intervention; This arm will be treated with double dosages of beta-lactam antibiotics the first 48 hours after inclusion.	Drug: Double dosing of beta-lactam antibiotic; This arm will receive double dosing of beta-lactam antibiotics for the first 48 hours after inclusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28-day mortality	From enrollment to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day mortality		From enrollment to 90 days
365-day mortality		From enrollment to the 365 days
ICU lengt of stay		From enrollment to the end of the study period at 12 months
Hospital lengt of stay		From enrollment to the end of the study period at 12 months
Time to shock reversal	From enrollment to the use of <0.1 gamma of vasopressors for 4 consecutive hours.	From enrollment to the end of the study period at 12 months
Microbiological eradication	Eradication of the causative organism from the primary source up to 30 days after therapy when confirmed by at least one repeated culture. In cases where there were no repeat cultures and the patient had resolution of the infection, microbial eradication will be presumed.	From enrollment to hospital discharge
Clinical cure	Completion of β-lactam antibiotic by day 14 without recommencement of antibiotics within 48hrs of cessation for same infective episode (investigator assessment of clinical response)	From enrollment to 14 days
Plasma concentrations of the beta-lactam antibiotics	Through concentrations take once a day for 3 consectutive days after enrollment. Target attianment is defined as 100%fT>4xMIC	From enrollment to day 3
Delta SOFA	SOFA at day 3 - SOFA at admission	From enrollment to day 3
Delta Lactate	Lactate at day 3 - lactate upon inclusion	From enrollment to day 3
Quality of life	EQ-5D-5L, a quetionnaire scoring 1 to 5 points on 5 domains. A higher score means a worse outcome.	3 and 12 months after inclusion
Medical consumption	iMTA Medical Consumption questionnaire	3 and 12 months after inclusion
Productivity	iMTA Productivity questionnaire	3 and 12 months after inclusion
Adverse events and toxicity		From enrollment until the end of the study period at 12 months

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Albert Schweitzer Hospital; Maasstad Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 27, 2024
• First Submitted That Met QC Criteria: January 8, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 8, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: septic shock; intensive care; critically ill; antibiotic; sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Critical Illness; Sepsis; Toxemia; Shock, Septic; Anti-Infective Agents; Beta Lactam Antibiotics; Anti-Bacterial Agents; Lactams; beta-Lactams
• Other Study ID Numbers: 2024-512950-13; 10140022310046 (Other Grant/Funding Number: ZonMW); 2024-512950-13-00 (Ctis); U1111-1308-9223 (Registry Identifier: WHO universal trial number (UTN))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No