None listed
Conditions
Brief summary
Liver transplant recipients are at high risk of antibiotic-resistant bacterial and fungal infections after transplant. In patients who are colonised with antibiotic-resistant superbugs, this study will test whether it is safe, feasible, and effective to adjust the antibiotics given at the time of liver transplant surgery to cover these superbugs, instead of following a “one-size-fits-all” approach where all patients receive the same antibiotics, regardless of whether they carry superbugs. In patients who are not colonised with antibiotic-resistant superbugs and are started on antifungal medications, this study will also test whether it is safe, feasible, and effective to give a fixed duration (five days) of antifungals compared to a clinician-guided duration after a minimum of five days. This is a small, early-stage study. The primary aim is to assess whether this type of study is feasible, including whether enough patients can be recruited, whether the study procedures can be carried out as planned, and whether sufficient high-quality data can be collected. In addition, two optional substudies will be undertaken at Austin Health and will be available only to participants enrolled at this site. The first will investigate the pharmacokinetic-pharmacodynamic properties of perioperative antimicrobial prophylaxis during liver transplantation. The second will evaluate longitudinal changes in the microbiome during the first 90 days following liver transplantation. The outcomes for the substudies will not be described as these are exploratory and specific to one site.
Interventions
This study comprises three domains:
1. Multidrug-resistant organism (MDRO) Antibiotic Prophylaxis Domain
2. Antifungal Prophylaxis Duration Domain
3. Observational Domain
Allocation of participants to study domains is determined by:
1. The result of the most recent MDRO colonisation swab a time of liver transplant surgery, and,
2. Whether the participant has commenced perioperative antifungal prophylaxis
MDRO Colonisation Swabs
MDRO colonisation swabs are obtained at:
- Study enrolment
- Hospi
This study comprises three domains: 1. Multidrug-resistant organism (MDRO) Antibiotic Prophylaxis Domain 2. Antifungal Prophylaxis Duration Domain 3. Observational Domain Allocation of participants to study domains is determined by: 1. The result of the most recent MDRO colonisation swab a time of liver transplant surgery, and, 2. Whether the participant has commenced perioperative antifungal prophylaxis MDRO Colonisation Swabs MDRO colonisation swabs are obtained at: - Study enrolment - Hospital admission for liver transplantation - Additional timepoints during routine clinical care outside the scope of the study. The timing of the most recent MDRO colonisation swab relative to transplantation may therefore vary between participants and may range from 1 day to several months prior to surgery. A positive MDRO colonisation swab is defined as detection of any of the following organisms: - Vancomycin-resistant Enterococcus (VRE) - Methicillin-resistant Staphylococcus aureus (MRSA) - Extended-spectrum beta-lactamase-producing Gram negative organisms (ESBL) - Carbapenem-resistant organisms (CRO). Domain Allocation Participants will be allocated to study domains as follows: - MDRO Antibiotic Prophylaxis Domain: participants whose most recent MDRO colonisation swab at the time of transplant surgery is POSITIVE. - Antifungal Prophylaxis Duration Domain: participants whose most recent MDRO colonisation swab is NEGATIVE and who commence perioperative antifungal prophylaxis from the time of transplantation until discharge from the Intensive Care Unit (ICU) - Observational Domain: all other participants, including: those ineligible for the MDRO antibiotic prophylaxis and antifungal prophylaxis duration domains, and those eligible for antifungal prophylaxis duration domain but with a positive MDRO colonisation swab. MDRO Antibiotic Prophylaxis Domain (i.e. participants with a positive MDRO colonisation swab) Intervention Group: MDRO guided prophylaxis Perioperative antibiotic prophylaxis at the time of liver transplantation determined by the most recent MDRO colonisation swab result. Prophylactic antibiotic regimens are as follows: - For MRSA: intravenous vancomycin 15mg/kg every 12 hours + piperacillin-tazobactam 4.5g every 6 hours until 24 hours post op. - For VRE: intravenous linezolid 600mg every 12 hours + piperacillin-tazobactam 4.5g every 6 hours until 24 hours post op. - For ESBL: intravenous meropenem 1g every 8 hours until 24 hours post op. - For CRO: choice of (1) intravenous amikacin 15mg/kg every 24 hours, or, intravenous gentamicin 4-5mg/kg every 24 hours, or intravenous tobramycin 4-5mg/kg every 24 hours, and, intravenous piperacillin-tazobactam 4.5g every 6 hours until 24 hours post-op; (2) intravenous ceftazidime-avibactam 2000mg/500mg every 8 hours + intravenous aztreonam 2g every 8 hours + intravenous ampicillin 2g every 6 hours + intravenous metronidazole 500mg every 12 hours until 24 hours post op; (3) intravenous colistin (dosed based on weight and renal function) every 12 hours + intravenous piperacillin-tazobactam 4.5g every 6 hours until 24 hours post op; (4) intravenous cefiderocol 2g every 8 hours + intravenous ampicillin 2g every 6 hours + intravenous metronidazole 500mg every 12 hours until 24 hours post op. Antifungal Prophylaxis Duration Domain (i.e. participants with a negative MDRO colonisation swab who receive perioperative antifungal prophylaxis) Intervention Group: Fixed Five-Day Duration Participants will receive a fixed five-day course of systemic antifungal prophylaxis following liver transplantation. The antifungal agent and dosing will be determined according to site-specific standard practice, but will commonly consist of intravenous anidulafungin 200mg loading dose followed by 100mg daily. Intervention Delivery and Adherence Note: Interventions will be administered by anaesthetic and intensive care staff according to group allocation. Adherence to allocated prophylactic regimens will be assessed through review of electronic medical records.
Sponsors
Austin Health
Study design
Allocation
Randomised controlled trial
Intervention model
Other
Primary purpose
Prevention
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Study Inclusion Criteria: 1. Aged 18 years or older at time of consent. 2. Listed on the liver transplant waitlist. MDRO Antibiotic Prophylaxis Domain Inclusion Criteria: 1. Undergo liver transplantation surgery, and 2. Most recent MDRO colonisation swab relative to liver transplantation surgery is positive. Antifungal Prophylaxis Duration Domain Inclusion Criteria: 1. Undergo liver transplantation surgery, and 2. Most recent MDRO colonisation swab relative to liver transplantation surgery is negative, and 3. Participant is started on perioperative antifungal prophylaxis from time of liver transplantation to Intensive Care Unit discharge. Observational Domain Inclusion Criteria: 1. Undergo liver transplantation surgery 2. Most recent MDRO colonisation swab relative to liver transplantation surgery is positive, but the participant did not enter the MDRO antibiotic prophylaxis domain (e.g. not randomised in time), or, 3. Most recent MDRO colonisation swab relative to liver transplantation surgery is negative, but the participant was not started on perioperative antifungal prophylaxis from time of liver transplantation to Intensive Care Unit discharge.
Exclusion criteria
Study Exclusion Crteria: None MDRO Antibiotic Prophylaxis Domain Exclusion Criteria: 1. Participants with a documented multi-drug resistant organism infection within 14 days prior to liver transplantation who are receiving systemic antimicrobial therapy active against the identified pathogen at the time of transplantation. 2. Participants with a documented history of severe hypersensitivity reaction (e.g. anaphylaxis or severe cutaneous adverse drug reaction) or any other clinically significant adverse reaction that would preclude the safe use of study-relevant antibiotics, including routine perioperative antibiotic prophylaxis or any agent included in the MDRO prophylaxis intervention arm (i.e. meropenem, linezolid, vancomycin, cefiderocol, ceftazidime-avibactam, aztreonam, colistin, gentamicin, tobramycin, amikacin, ampicillin, metronidazole). 3. Participants with any medical condition or circumstance that, in the opinion of the investigator, would substantially increase the risk associated with study participation. Antifungal Prophylaxis Duration Domain Exclusion Criteria: 1. Participants with a documented invasive fungal infection diagnosed within 14 days prior to liver transplantation who are receiving systemic antifungal therapy active against the identified pathogen at the time of transplantation. 2. Participants with any medical condition or circumstance that, in the opinion of the investigator, would substantially increase the risk associated with study participation. Observational Domain Exclusion Criteria None
Outcome results
None listed