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.
Adult (≥18 years) patients colonized with Carbapenemase-Producing Enterobacterales (CPE) undergoing liver transplantation (LT)
Informed consent signed by the enrolled patients
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
Crossover
Ceftazidime - Avibactam ( CAZ-AVI)
Drug2g/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
Meropenem-Vaborbactam
Drug1g/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.
Imipenem+Relebactam
DrugSupplied 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.
Cefiderocol
DrugSupplied 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.
Aztreonam
DrugSupplied 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.
Eravacycline
DrugSupplied 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.
Aztreonam-Avibactam
DrugSupplied 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.
Amoxi Clavulanate
DrugPowder 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.
Piperacillin + Tazobactam
DrugPowder 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.
Tigecycline
DrugPowder 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.
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.
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
Cross-sectional differences between T-PAP and S-PAP groups over time, in GM alpha diversity, composition (relative abundance at different taxonomic levels) and functionality (gene and pathway abundances), will be assessed using the Kruskal-Wallis test, followed by post-hoc Wilcoxon rank-sum tests.
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
In order to evaluate the relationship between the attainment of early optimal PK/PD target with agents used for both T-PAP and S-PAP and the occurrence of CPE and non-CPE infections in the post-LT period, TDM of selected agents will be performed at the end of surgical procedure and at 24 hours after starting T-PAP and S-PAP. The relationship between the attainment of optimal PK/PD target and the occurrence of CPE and non-CPE infections will be calculated comparing the percentage of patients developing CPE and non-CPE infections in the first two weeks after LT in the intervention and control group.
To investigate the impact of T-PAP vs. S-PAP on CPE carriage status
The impact of T-PAP vs S-PAP on CPE carriage status will be calculated comparing the percentage of patients colonized with Carbapenem-producing Enterobacterales (CPE) at 30, 60 and 90 days after LT in the intervention and control group.
To investigate the development of bacterial infections
The impact of T-PAP vs S-PAP will be calculated comparing the percentage of patients diagnosed with a bacterial infection at 30, 60 and 90 days after LT in the intervention and control group.
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