Liver Transplant, Carbapenem-resistant Enterobacterales, CRE Colonization
Conditions
Keywords
CRE colonization, liver transplant, stepped-wedge cluster randomized trial, therapeutic drug monitoring, gut microbiome, carbapenem-resistant enterobacterales
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.
Detailed description
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.
Interventions
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
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.
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.
DRUGCefiderocol
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.
DRUGAztreonam
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.
DRUGEravacycline
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.
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.
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.
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.
DRUGTigecycline
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
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult (≥18 years) patients colonized with Carbapenemase-Producing Enterobacterales (CPE) undergoing liver transplantation (LT) * Informed consent signed by the enrolled patients
Exclusion criteria
* 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | Within 14 days from liver 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 | At 30, 60 and 90 days after liver transplant | 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 | At 30, 60 and 90 days after liver transplant | 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. |
| To investigate all-cause mortality | At 30, 60 and 90 days after liver transplant | The impact of T-PAP vs S-PAP will be calculated comparing the percentage of patients who died from any cause at 30, 60 and 90 days after LT in the intervention and control group. |
| To investigate the safety of T-PAP versus S-PAP | During prophylaxis administration or within 7 days from the initiation of administration | The rates of adverse events (e.g. neurotoxicity) in the intervention and in the control groups will be computed. |
Countries
Italy
Contacts
CONTACTMaddalena Giannella, MD, PhD
CONTACTMatteo Rinaldi, MD
PRINCIPAL_INVESTIGATORMaddalena Giannella, MD, PhD
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Outcome results
None listed