Targeted Versus Standard Peri-operative Antibiotic Prophylaxis in Patients Colonized With Carbapenemase Producing Enterobacterales Undergoing Liver Transplantation

NCT07759453 | Not Yet Recruiting Phase 3

• 2 other identifiers: TAILOR2025-523453-34-00
• Study Type: interventional
• Target: 168
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Liver Transplant; Carbapenem-resistant Enterobacterales; CRE Colonization

Keywords

CRE colonization; liver transplant; stepped-wedge cluster randomized trial; therapeutic drug monitoring; gut microbiome; carbapenem-resistant enterobacterales

Outcome Measures

Primary Outcomes (1)

• 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

  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.

  Within 14 days after liver transplant

Secondary Outcomes (6)

• 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 the development of bacterial infections

  At 30, 60 and 90 days after liver transplant

• To investigate all-cause mortality

  At 30, 60 and 90 days after liver transplant

Study Arms (2)

Targeted prophylaxis T-PAP

EXPERIMENTAL

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

Drug: Ceftazidime - Avibactam ( CAZ-AVI); Drug: Meropenem-Vaborbactam; Drug: Imipenem+Relebactam; Drug: Cefiderocol; Drug: Aztreonam; Drug: Eravacycline; Drug: Aztreonam-Avibactam

Standard prophylaxis S-PAP

EXPERIMENTAL

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

Drug: Amoxi Clavulanate; Drug: Piperacillin + Tazobactam; Drug: Tigecycline

Interventions

Ceftazidime - Avibactam ( CAZ-AVI) DRUG

2g/0.5g powder for concentrate for solution for infusion.Each vial contains ceftazidime pentahydrate equivalent to 2 g ceftazidime and avibactam sodium equivalent to 0.5 g avibactam. For T-PAP, the administration should not exceed 48 hours

Targeted prophylaxis T-PAP

Meropenem-Vaborbactam DRUG

1g/1g powder for concentrate for solution for infusion. Each vial contains meropenem trihydrate equivalent to 1 g meropenem, and 1 g vaborbactam. Excipient with known effect: Each vial contains 10.9 mmol of sodium (approximately 250 mg). For T-PAP, the administration should not exceed 48 hours.

Targeted prophylaxis T-PAP

Imipenem+Relebactam DRUG

Supplied as a dry powder in a single-dose vial that must be constituted and further diluted using aseptic technique prior to intravenous infusion (IV). Each vial contains imipenem monohydrate equivalent to 500 mg imipenem, cilastatin sodium equivalent to 500 mg cilastatin, and relebactam monohydrate equivalent to 250 mg relebactam. For T-PAP, the administration should not exceed 48 hours.

Targeted prophylaxis T-PAP

Cefiderocol DRUG

Supplied as single use vials containing cefiderocol sodium tosylate, equivalent to 1 g cefiderocol. Excipients include sucrose, sodium chloride and sodium hydroxide. For T-PAP, the administration should not exceed 48 hours.

Targeted prophylaxis T-PAP

Aztreonam DRUG

Supplied as a single use vials containing sterile solution of Aztreonam and Arginine and a suitable osmolality adjusting substance in Water for Injection. It contains NLT 90.0% and NMT 120.0% of the labeled amount of aztreonam. For T-PAP, the administration should not exceed 48 hours.

Targeted prophylaxis T-PAP

Eravacycline DRUG

Supplied as powder for concentrate for solution for infusion, each vial contains 50 mg of eravacycline. Each vial is for single use only, that must be reconstituted and further diluted using aseptic technique prior to intravenous infusion. For T-PAP, the administration should not exceed 48 hours.

Targeted prophylaxis T-PAP

Aztreonam-Avibactam DRUG

Supplied as powder for concentrate for solution for infusion, each vial contains 1.5 g of aztreonam and avibactam sodium equivalent to 0.5 g of avibactam. For T-PAP, the administration should not exceed 48 hours.

Targeted prophylaxis T-PAP

Amoxi Clavulanate DRUG

Powder for solution for injection or infusion, supplied as vials of 2000/200 mg. Each vial contains 2000 mg amoxicillin (as amoxicillin sodium) and 200 mg clavulanic acid (as potassium clavulanate). Each vial contains 5.5 mmol (125.9 mg) of sodium and 1 mmol (39.3 mg) of potassium. For S-PAP, the duration should not exceed 48 hours.

Standard prophylaxis S-PAP

Piperacillin + Tazobactam DRUG

Powder for solution, each vial contains amounts of Piperacillin Sodium and Tazobactam Sodium equivalent to not less than 90.0 percent and not more than 110.0 percent of the labeled amounts of piperacillin, the labeled amounts representing proportions of piperacillin to tazobactam is of 8 : 1. It may contain small amounts of a suitable buffer stabilizer. For S-PAP, the duration should not exceed 48 hours.

Standard prophylaxis S-PAP

Tigecycline DRUG

Powder for solution, each vial should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, or 5% Dextrose Injection, to achieve a concentration of 10 mg/mL of tigecycline. For S-PAP, the duration should not exceed 48 hours.

Standard prophylaxis S-PAP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult (≥18 years) patients colonized with Carbapenemase-Producing Enterobacterales (CPE) undergoing liver transplantation (LT)
• Informed consent signed by the enrolled patients

You may not qualify if:

• 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)

Sponsors & Collaborators

• IRCCS Azienda Ospedaliero-Universitaria di Bologna: lead

Study Sites (3)

Irccs Azienda Ospedaliero-Universitaria Di Bologna

Bologna, BO, 40138, Italy

Location

Azienda Ospedaliero Universitaria Pisana

Pisa, PI, 56126, Italy

Location

Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino

Torino, TO, 10126, Italy

Location

MeSH Terms

Interventions

avibactam, ceftazidime drug combination; meropenem and vaborbactam; imipenem, cilastatin and relebactam; Cefiderocol; Aztreonam; eravacycline; Amoxicillin-Potassium Clavulanate Combination; Piperacillin, Tazobactam Drug Combination; Tigecycline

Intervention Hierarchy (Ancestors)

Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Monobactams; Heterocyclic Compounds, 1-Ring; Clavulanic Acid; Clavulanic Acids; Amoxicillin; Ampicillin; Penicillin G; Penicillins; Drug Combinations; Pharmaceutical Preparations; Tazobactam; Penicillanic Acid; Piperacillin; Sulfones; Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Study Officials

• Maddalena Giannella, MD, PhD

  IRCCS Azienda Ospedaliero-Universitaria di Bologna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maddalena Giannella, MD, PhD

CONTACT

+39 051 2143199; maddalena.giannella@unibo.it

Matteo Rinaldi, MD

CONTACT

+39 051 2143595; matteo.rinaldi@aosp.bo.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A stepped-wedge cluster randomized trial will be conducted over a 2-year period at three hospitals. The trial will be structured into four phases, each lasting six months. During phase 1 (pre-rollout), all clusters (i.e. hospitals) will use S-PAP for all patients. In each of the phases 2 to 4 one cluster will transition to T-PAP, so that in phase 4 all clusters will use T-PAP. Cluster transitions from S-PAP to T-PAP will be determined by centrally performed computer generated randomization by an independent statistician, ensuring equal probability of assignment and minimizing selection bias. The randomization sequence will be generated prior to study initiation and kept confidential until implementation.

Study Record Dates

• First Submitted: June 19, 2026
• First Posted: August 12, 2026
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): September 30, 2029
• Last Updated: August 12, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3)