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

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

Interventions

DRUG

Ceftazidime - Avibactam ( CAZ-AVI)

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

DRUG

Meropenem-Vaborbactam

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.

DRUG

Imipenem+Relebactam

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.

DRUG

Cefiderocol

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.

DRUG

Aztreonam

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.

DRUG

Eravacycline

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.

DRUG

Aztreonam-Avibactam

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.

DRUG

Amoxi Clavulanate

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.

DRUG

Piperacillin + Tazobactam

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.

DRUG

Tigecycline

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.

Sponsors & Collaborators

• IRCCS Azienda Ospedaliero-Universitaria di Bologna

  lead OTHER

Principal Investigators

• Maddalena Giannella, MD, PhD · IRCCS Azienda Ospedaliero-Universitaria di Bologna

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-10-01

Primary Completion

2029-06-30

Completion

2029-09-30

Countries

• Italy

Study Locations