Evaluation of Beta-lactam Intermittent vs. Continuous Infusion and Combination Antibiotic Therapy in ICU Patients with Hospital-acquired Sepsis
- Trial ID
- 2024-516849-39-01
- Protocol
- APHP180596
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **30-day mortality** of patients with hospital-acquired **sepsis** in the intensive care unit (ICU) based on the mode of administration of the pivotal beta-lactam (βL) antibiotic, specifically contrasting continuous infusion (CID) with intermittent infusion (IID). This objective is clinically relevant as it aims to determine the most effective administration method to reduce mortality in critically ill patients with sepsis, a condition associated with high morbidity and mortality rates.
Secondary objectives include evaluating:
- 30-day mortality in patients with proven Gram-negative infection (GNI), non-fermentative GNI, and GNI with minimum inhibitory concentration (MIC) of βL higher than EUCAST breakpoints.
- 30-day mortality in patients receiving non-carbapenem-βL and clinical failure rates.
- Pharmacokinetic-pharmacodynamic (PK-PD) target attainment at days 1 and 3.
- Superinfection or new infection at day 30 due to Gram-negative bacteria (GNB) resistant to the administered βL.
- Microbiological failure among patients with clinical failure.
- New carriage, colonization, or infection with specific resistant GNB at days 3, 7, and 30.
- Duration of organ failure between day 1 and day 30, occurrence of adverse events at day 30, length of ICU and hospital stays, and 180-day mortality.
Participants
The clinical trial focuses on **antibiotic therapy in sepsis**, specifically targeting patients with hospital-acquired sepsis in the ICU. The study population includes both male and female adults aged 18 years and older. Participants are required to have been hospitalized for more than 48 hours or discharged less than 48 hours ago, with sepsis diagnosed within the last 24 hours. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include specific risk factors for gram-negative multidrug-resistant pathogens, such as prior intravenous antibiotic use, prolonged hospital stays, mechanical ventilation, and the presence of indwelling devices. Lifestyle considerations such as recent travel to high-risk geographical areas and exposure to certain antibiotics are also relevant. Participants are expected to have an ICU stay of more than three days, and appropriate bacteriological sampling must be performed before starting antimicrobial therapy.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of different **antibiotic** administration methods in patients with hospital-acquired sepsis in the intensive care unit (ICU). This is a randomized, double-blind, controlled trial comparing the 30-day mortality rate between two groups: those receiving continuous infusion of beta-lactam antibiotics (CID group) and those receiving intermittent infusion (IID group). The trial is expected to commence on December 4, 2024, and conclude by September 4, 2026.
Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (≥ 18 years), diagnosis of sepsis within the last 24 hours, and specific risk factors for gram-negative multidrug-resistant pathogens. Follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur at day 30, where the primary endpoint, mortality rate, will be evaluated.
The expected duration of participant involvement is up to 30 days, with the possibility of early termination if adverse events related to the trial treatment occur, or if the participant requires rescue therapy for the trial pathogen. Secondary endpoints include clinical failure, PK-PD target attainment, and the incidence of superinfection or new nosocomial infections. The trial will also assess organ failures, length of ICU and hospital stays, and mortality rate at day 180. Participants will be closely monitored throughout the study to ensure safety and adherence to the protocol.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **AVIBACTAM** is provided as a solution for infusion, with a maximum daily dose of 1500 mg and a total dose of 10500 mg over a 7-day period. It is administered via injection. **CEFTAZIDIME** is also used in the trial, available as a solution for injection, with a maximum daily dose of 6 g and a total dose of 6 g over 7 days, administered via injection. **TAZOBACTAM** is provided as a powder for solution for injection/infusion, with a maximum daily dose of 2 g and a total dose of 14 g over 7 days, administered via injection.
**CEFTOLOZANE** is administered as a solution for infusion, with a maximum daily dose of 6 g and a total dose of 6 g over 7 days, via injection. **PIPERACILLIN** is available as a solution for injection, with a maximum daily dose of 16 g and a total dose of 16 g over 7 days, administered via injection. **CEFEPIME** is provided as a solution for injection/infusion, with a maximum daily dose of 6 g and a total dose of 6 g over 7 days, administered via injection.
**AMIKACIN** is administered as a solution for infusion, with a maximum daily dose of 30 mg/kg and a total dose of 150 mg/kg over 5 days, via injection. **MEROPENEM** is provided as a powder for infusion, with a maximum daily dose of 6 g and a total dose of 42 g over 7 days, administered via injection. **LINEZOLID** is administered as a solution for infusion, with a maximum daily dose of 6 g and a total dose of 6 g over 7 days, via infusion.
**CEFTAZIDIME AND BETA-LACTAMASE INHIBITOR** is provided as a solution for infusion, with a maximum daily dose of 6 g and a total dose of 42 g over 7 days, administered via infusion. **PIPERACILLIN AND BETA-LACTAMASE INHIBITOR** is administered as a solution for infusion, with a maximum daily dose of 16 g and a total dose of 112 g over 7 days, via infusion. **CEFTOLOZANE AND BETA-LACTAMASE INHIBITOR** is provided as a solution for infusion, with a maximum daily dose of 6 g and a total dose of 42 g over 7 days, administered via infusion.
Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules. The trial aims to compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU, focusing on the mode of administration of the pivotal β-lactam antibiotic.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of the mortality rate at day 30 between two groups: the Continuous Infusion of **β-lactam** (CID) group and the Intermittent Infusion of **β-lactam** (IID) group. This primary endpoint will provide a direct measure of the treatment's impact on survival in patients with hospital-acquired sepsis in the ICU.
Secondary endpoints will include a detailed analysis of mortality rates at day 30 in specific subgroups, such as patients with proven Gram-negative infections (GNI) and those with non-carbapenem-**β-lactam** treatments. Clinical failure will be assessed based on criteria such as death during or shortly after trial therapy, the need for rescue therapy, adverse events leading to trial withdrawal, persistent bacteremia, and lack of improvement in clinical conditions like shock or pneumonia.
Additional secondary endpoints will involve pharmacokinetic-pharmacodynamic (PK-PD) target attainment rates, evaluated at specific time points such as day 1 and day 3, and the percentage of patients experiencing superinfection or new nosocomial infections. The trial will also monitor the emergence of new carriage of multidrug-resistant Gram-negative bacteria (MDR-GNB) and organ failures, assessed by the AUCSOFA score from day 1 to day 30. Other measures include the length of ICU and hospital stays, the percentage of patients with encephalopathy or renal failure, and the mortality rate at day 180.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adults (≥ 18 years) • Hospital-acquired sepsis (according to sepsis 3.0 definitions) - Patient hospitalized for more than 48 hours OR Patient discharged less than 48 hours ago - AND sepsis diagnosed within the last 24 hours
- •One of the following risk factors for gram negative multidrug resistant pathogens: -Prior intravenous antibiotic use within 7 days prior to sepsis onset with the exception of antibiotic effective only against Gram-positive bacteria, penicillin A and macrolides -Prolonged hospital stay (≥ 15 days of hospitalization) within 3 months prior to sepsis onset Prolonged mechanical ventilation (≥ 5 days on mechanical ventilation) within 3 months prior to sepsis onset-Patients with indwelling devices (dialysis access lines, intravascular lines, urinary catheter, endotracheal or tracheostomy tube, gastrostomy or jejunostomy feeding tube)
- Patients known to be infected, colonized or carriers of MDR gram negative bacteria within 3 months prior to sepsis onset - Exposure to an antibiotic (amoxicillin-clavulanic acid, C2G, C3G, fluoroquinolones) within 3 months prior to sepsis onset - A trip abroad to known geographical areas at risk (in particular the Indian subcontinent, South-East Asia, the Middle East and North Africa, the Mediterranean Basin) within 3 months prior to sepsis onset - A functional or organic abnormality of the urinary tract in case of urinary tract infection. • Appropriate bacteriological sampling performed before starting antimicrobial therapy • Expected stay in ICU of more than 3 days
Exclusion Criteria
- A priori known resistance to all the proposed beta-lactams or to amikacin Need for extrarenal treatment at inclusion according to the criteria of Gaudry et al. • Known hypersensitivity to ceftazidime, piperacillin-tazobactam, cefepime, meropenem, ceftazidime-avibactam, ceftazolane-avibactam or to any of the excipients included in the corresponding pharmaceutical drugs, • Known hypersensitivity to any cephalosporin antibacterial agent, • Know hypersentitivity to any penem antibacterial agent,
- Severe known hypersensitivity (eg, anaphylactic reaction, severe skin reaction) to any other beta-lactam antibiotic (eg, penicillins or monobactam ) or to any of its excipients. • Known contraindication to the aminoglycoside family including o Hypersensitivity to the active substance, to any aminoglycoside antibacterial agent or to any of the excipients included in the corresponding pharmaceutical drugs, o Cirrhosis of grades B and C according to the Child-Pugh classification. o Myasthenia gravis. o Simultaneous administration of another aminoglycoside o Association with ataluren
- Non-complicated urinary tract infection (corresponding to a positive ECBU not responsible for sepsis) • Bone marrow transplant or chemotherapy-induced neutropenia • Infections for which long-term antibiotic treatment > 8 days is strongly recommended (i.e., infective endocarditis, osteoarticular infections, anterior mediastinitis after cardiac surgery, hepatic or cerebral abscesses, chronic prostatitis for instance • Presence of antibiotic therapy for the new sepsis (if sepsis acquired in the hospital outside the resuscitation> 2 doses of antibiotics or > 16h for continuous infusion)
- Limitation of life support (comfort care applied only) at the time of screening • Enrolment to another interventional drug study • Pregnancy or breastfeeding • Subject deprived of freedom, subject under a legal protective measure • Non affiliation to any health insurance system • Refusal to participate to the study (patient or legal representative or family member or close relative if present)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 04 Dec 2024 | 600 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CEFTAZIDIME | Comparator | — | INJECTION | 6 | 7 | SUB07422MIG |
PIPERACILLIN | Comparator | — | INJECTION | 16 | 7 | SUB09867MIG |
CEFTAZIDIME AND BETA-LACTAMASE INHIBITOR | Test | PHF00230MIG | INFUSION | 6 | 7 | SCP13237974 |
CEFTOLOZANE | Comparator | — | INJECTION | 6 | 7 | SUB167762 |
CEFTAZIDIME | Comparator | — | INJECTION | 12 | 7 | SUB07422MIG |
CEFEPIME | Test | PHF675 | INFUSION | 6 | 7 | SCP107177473 |
CEFEPIME | Comparator | — | INJECTION | 6 | 7 | SUB07390MIG |
MEROPENEM | Test | PHF00230MIG | INFUSION | 6 | 7 | SCP101876674 |
TAZOBACTAM | Comparator | — | INJECTION | 3 | 7 | SUB10849MIG |
TAZOBACTAM | Comparator | — | INJECTION | 2 | 7 | SUB10849MIG |