Targeted Versus Standard Peri-operative Antibiotic Prophylaxis in Patients Colonized With Carbapenemase-producing Enterobacterales Undergoing Liver Transplantation: a Stepped Wedge Cluster Randomization Trial
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 168
- 试验地点
- 3
- 主要终点
- To investigate the impact of T-PAP vs. S-PAP on the incidence of early CPE infection after LT in patients colonized with CPE undergoing LT
研究概览
简要总结
This is a multicenter stepped-wedge cluster randomized trial, conducted over a 2-year period at three hospitals. The trial is structured into four phases, each lasting six months. During phase 1 (pre-rollout), all hospitals will use standard antibiotic prophylaxis for all patients. In each of phases 2 to 4, one hospital will switch to targeted antibiotic prophylaxis, so that by phase 4 all hospitals will be using it. The order in which hospitals switch is determined by computer-generated randomization performed centrally by an independent statistician, ensuring each hospital has an equal chance of switching at any given phase and minimizing selection bias.
The goal of this clinical trial is to learn whether targeted antibiotic prophylaxis works better than standard antibiotic prophylaxis at preventing infections in liver transplant patients who carry resistant bacteria called CPE (carbapenemase-producing Enterobacterales). It will also learn about the effects of these antibiotics on gut bacteria.
The main questions it aims to answer are:
- Does targeted antibiotic prophylaxis reduce the number of CPE infections occurring in the first two weeks after liver transplant, compared to standard prophylaxis?
- How do targeted and standard antibiotic prophylaxis affect the gut microbiome after transplant?
- Is there a link between achieving optimal antibiotic blood levels and the risk of developing an infection after transplant?
Researchers will compare targeted antibiotic prophylaxis (chosen based on the specific bacteria each patient carries) to standard antibiotic prophylaxis (used routinely at each hospital) to see which approach better prevents infection.
This study does not involve the administration of any drugs or instrumental examinations beyond those already part of standard clinical care at each center. However, additional blood tests will be performed by collecting one extra blood sample (and a bile sample, if the patient has a Kehr's tube, which is a drain placed in the bile duct after surgery) during blood draws already scheduled as part of routine clinical practice, in order to measure drug levels in the blood. Stool samples will also be collected specifically for the study to investigate the gut microbiome.
详细描述
Colonization and infection with carbapenemase-producing Enterobacterales (CPE) have been associated with significant morbidity and mortality in the setting of solid organ transplantation (SOT), and in particular among liver transplant (LT) candidates and/or recipients. Indeed, the prevalence of CPE infection is highest after LT compared with other types of SOT, CPE carriage is the strongest predisposing factor, and CPE carriage/infection has been associated with significant increase in the odds of death across multiple studies. Several strategies have been proposed to reduce CPE infection and associated poor outcome after LT, including active screening, decolonization and targeted perioperative antibiotic prophylaxis (T-PAP). Decolonization is no longer recommended due to its limited benefit and associated adverse events, observed also in a randomized controlled trial on SOT recipients. Recent European guidelines endorsed the performance of active screening for CPE carriage before LT but, due to the lack of evidence, they could not provide a recommendation regarding optimal PAP in CPE carriers. This study addresses a critical unmet need in liver transplantation by evaluating targeted perioperative antibiotic prophylaxis (T-PAP) versus standard perioperative antibiotic prophylaxis (S-PAP) in CPE colonized patients. By using a stepped-wedge cluster-randomized design, it could generate robust, practice-changing evidence on how to reduce early CPE infections, mortality, and healthcare costs. The project is innovative in study design as well as in integrating advanced gut microbiome (GM) and resistome analyses, offering new insights into the GM effects of perioperative antibiotic strategies. The use of therapeutic drug monitoring (TDM) to optimize dosing adds a precision medicine approach. Findings are expected to impact clinical guidelines and improve outcomes for transplant recipients and potentially for other high-risk surgical populations.
The stepped-wedge design is better suited than standard individual randomization for evaluating the potential indirect effects of the T-PAP policy on gut microbiome and liver functionality.
The intervention will consist of targeted perioperative antibiotic prophylaxis (T-PAP) using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting. In the control arm, standard perioperative antibiotic prophylaxis (S-PAP) will be administered according to local protocols. In both arms, prophylaxis will begin 30-60 minutes before surgical incision, following guidelines, and will be discontinued no later than 48 hours post-surgery.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult (≥18 years) patients colonized with Carbapenemase-Producing Enterobacterales (CPE) undergoing liver transplantation (LT)
- •Informed consent signed by the enrolled patients
排除标准
- •Active infection from any Gram-negative bacteria at the time of LT
- •High risk of donor-derived CPE infection (e.g., donors known to be colonized or infected with CPE at the time of death, or CPE isolated from donor blood or preservation fluid samples)
- •Hypersensitivity to the active substance or to any of the excipients
- •Pregnancy and breastfeeding
- •Participation in a clinical trial in which an investigational drug was administered within 30 days of screening or within the 5 half-lives of the study drug, whichever is longer.
- •History of severe immediate hypersensitivity reactions (e.g., anaphylaxis) to beta-lactam agents (e.g., cephalosporins, carbapenems, or monobactams).
- •Colonization by strains resistant to all Investigational Medicinal Products (IMPs)
研究组 & 干预措施
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Meropenem-Vaborbactam (Drug)
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Imipenem+Relebactam (Drug)
Standard prophylaxis S-PAP
Patients include in the Standard prophylaxis (S-PAP) arm will be treated with standard drugs administered according to local protocols.
Drugs used as S-PAP are:
- Amoxicillin/clavulanate
- Piperacillin/tazobactam
- Tigecycline
干预措施: Amoxi Clavulanate (Drug)
Standard prophylaxis S-PAP
Patients include in the Standard prophylaxis (S-PAP) arm will be treated with standard drugs administered according to local protocols.
Drugs used as S-PAP are:
- Amoxicillin/clavulanate
- Piperacillin/tazobactam
- Tigecycline
干预措施: Piperacillin + Tazobactam (Drug)
Standard prophylaxis S-PAP
Patients include in the Standard prophylaxis (S-PAP) arm will be treated with standard drugs administered according to local protocols.
Drugs used as S-PAP are:
- Amoxicillin/clavulanate
- Piperacillin/tazobactam
- Tigecycline
干预措施: Tigecycline (Drug)
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Aztreonam-Avibactam (Drug)
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Cefiderocol (Drug)
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Aztreonam (Drug)
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Ceftazidime - Avibactam ( CAZ-AVI) (Drug)
Targeted prophylaxis T-PAP
Patients included in the Targeted prophylaxis (T-PAP) arm will be treated using an agent shown to be active in vitro against the colonizing strain. The specific drug will be selected at the discretion of the local investigator, in collaboration with the attending physician, and, if necessary, discussed with all the study investigators in a dedicated meeting.All drugs will be used strictly in accordance with their approved Summary of Product Characteristics (SmPC).
Available drugs that could be used as a T-PAP are:
- Ceftazidime/avibactam
- Meropenem/vaborbactam
- Imipenem/relebactam
- Cefiderocol
- Aztreonam
- Eravacycline
- Aztreonam/avibactam
干预措施: Eravacycline (Drug)
结局指标
主要结局
To investigate the impact of T-PAP vs. S-PAP on the incidence of early CPE infection after LT in patients colonized with CPE undergoing LT
时间窗: Within 14 days after liver transplant
The impact of T-PAP over S-PAP will be calculated comparing the percentage of CPE infections in the first two weeks after LT in the intervention and control group.
次要结局
- To investigate the development of bacterial infections(At 30, 60 and 90 days after liver transplant)
- To investigate the impact of T-PAP vs. S-PAP on the dynamics of gut microbiome after LT in patients colonized with CPE at transplant(At the time of liver transplant, and at 14, 30, 60 and 90 days after liver transplant)
- To investigate the relationship between the attainment of optimal pharmacokinetics/pharmacodynamics (PK/PD) target and the occurrence of CPE and non-CPE infections after LT in patients colonized with CPE at transplant(Within 14 days from liver transplant)
- To investigate the impact of T-PAP vs. S-PAP on CPE carriage status(At 30, 60 and 90 days after liver transplant)
- To investigate all-cause mortality(At 30, 60 and 90 days after liver transplant)
- To investigate the safety of T-PAP versus S-PAP(During prophylaxis administration or within 7 days from the initiation of administration)