Kidney Transplant Infection, Bloodstream Infection, Kidney Transplant, Kidney Transplant Recipients, Infection, Urinary Tract Infection(UTI), Urinary Tract Infection Bacterial, Antibiotic Prophylaxis, Bacteriuria
Conditions
Keywords
kidney transplantation, bloodstream infection, urinary tract infection, antibiotic prophylaxis, pivmecillinam, bacteriuria, Enterobacterales
Brief summary
Kidney transplant recipients take medicines that suppress the immune system to prevent rejection of the transplanted kidney. As a result, they have a high risk of infections, especially urinary tract infections (UTIs). Some of these infections can spread to the bloodstream and cause serious illness, hospitalization, loss of kidney function, or death. Currently, there is no established strategy to prevent these serious bacterial infections in kidney transplant recipients who are at highest risk. The PREDICT study is investigating whether a low daily dose of the antibiotic pivmecillinam can reduce the risk of bacterial urinary tract infections and bloodstream infections after kidney transplantation. The study focuses on kidney transplant recipients who have bacteria detected in their urine during the first month after transplantation, as previous research suggests that these patients have a particularly high risk of developing serious infections later. In this randomized, double-blind, placebo-controlled trial, 180 adult kidney transplant recipients will be assigned by chance to receive either pivmecillinam or a matching placebo from 1 to 6 months after transplantation. Neither participants nor study staff will know which treatment has been assigned during the study. All participants will continue to receive standard post-transplant care and monitoring. The main goal of the study is to determine whether prophylactic pivmecillinam can reduce the occurrence of infections caused by Enterobacterales bacteria, including urinary tract infections and bloodstream infections, during the first 6 months after transplantation. The study will also evaluate the effects of treatment on serious clinical outcomes, safety, quality of life, antimicrobial resistance, and long-term kidney transplant outcomes. The study hypothesis is that targeted antibiotic prophylaxis with pivmecillinam in kidney transplant recipients at increased risk of infection will reduce the incidence of Enterobacterales urinary tract infections and bloodstream infections during the high-risk period after transplantation compared with placebo.
Detailed description
Background: Kidney transplant recipients are at increased risk of infectious complications because immunosuppressive treatment is required to prevent rejection of the transplanted kidney. Urinary tract infections are among the most common infectious complications after transplantation and may lead to bloodstream infections, which are associated with substantial morbidity, mortality, and risk of graft loss. Despite this burden, there is currently no established targeted strategy to prevent serious bacterial infections in kidney transplant recipients at highest risk of infection. Previous work by the investigators demonstrated that bacteriuria during the first month after kidney transplantation is an important predictor of subsequent urinary tract infections and bloodstream infections. Early bacteriuria therefore represents a clinically useful marker for identifying a high-risk subgroup that may benefit from preventive interventions. Study rationale: The PREDICT study evaluates a risk-stratified prophylactic strategy using pivmecillinam in kidney transplant recipients with early bacteriuria. Pivmecillinam is a narrow-spectrum oral antibiotic with activity against Enterobacterales, which are the predominant causes of urinary tract infections and bloodstream infections after kidney transplantation. Its pharmacological profile and extensive clinical experience make it a potential candidate for targeted prevention during the period of highest infection risk after transplantation. Objectives: The primary objective is to determine whether prophylactic pivmecillinam reduces the occurrence of Enterobacterales urinary tract infections and/or bloodstream infections in high-risk kidney transplant recipients. Secondary objectives include evaluation of all bloodstream infections, severe clinical outcomes, treatment safety, antimicrobial resistance, and patient-reported quality of life. Exploratory objectives include investigation of microbiome and resistome changes, immunological and metabolic biomarkers, and long-term transplant outcomes. Study Design: PREDICT is a Danish nationwide multicentre randomized, double-blind, placebo-controlled trial. Adult kidney transplant recipients with bacteriuria during the first month after transplantation will be randomly assigned to receive prophylactic pivmecillinam or placebo in addition to standard post-transplant care. Participants will be followed during the intervention period and for safety evaluation after treatment completion. Long-term outcomes will be assessed through national registry follow-up.
Interventions
DRUGPivmecillinam
Study participants in the intervention arm will receive 400 mg pivmecillinam tablets once daily administered orally. Treatment will be initiated one month post-transplantation and will continue for a total duration of 5 months (months 1-6 post-transplantation).
DRUGPlacebo
Study participants in the placebo arm will receive one inactive placebo tablet once daily; the timing, frequency and duration is the same as for the active study drug.
Sponsors
Susanne Dam Nielsen, MD, DMSc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years. 2. Kidney transplant recipient. 3. Able to provide written informed consent. 4. ≥1 urine sample with bacteriuria ≥10\^5 CFU/mL (excluding fungi) within first month post-transplantation.
Exclusion criteria
1. Known strictures in the esophagus and/or obstructions in the gastrointestinal tract including diabetes gastroparesis. 2. Known hypersensitivity or allergy to β-lactam antibiotics. 3. Known or suspected genetic metabolism anomalies in the carnitine metabolism, including carnitine transporter defect or organic acidurias such as methylmalonic aciduria or propionic acidaemia. 4. Individuals of Faroese descent (defined as both biological parents born in the Faroe Islands). 5. Porphyria. 6. Current treatment with valproic acid, valproate or other medications liberating pivalic acid. 7. Current treatment with probenecid. 8. Current treatment with methotrexate. 9. Ongoing dialysis one month post-transplantation. 10. Pregnancy or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Enterobacterales Urinary Tract Infections and/or Enterobacterales Bloodstream Infections | Months 1-6 post-transplantation | Cumulative incidence of participants experiencing at least one Enterobacterales urinary tract infection and/or Enterobacterales bloodstream infection during months 1-6 post-transplantation, i.e., composite endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Enterobacterales Bloodstream Infection | Months 1-6 post-transplantation | Time to first occurrence of Enterobacterales bloodstream infection during months 1-6 post-transplantation |
| Time to All-Cause Mortality | Months 1-6 post-transplantation | Time to death of any cause during months 1-6 post-transplantation |
| Time to First Hospital Admission | Months 1-6 post-transplantation | Time to first hospital admission during months 1-6 post-transplantation |
| Time to Graft Loss | Months 1-6 post-transplantation | Time to graft loss during months 1-6 post-transplantation |
| Time to ≥50% Decrease in eGFR From Baseline | Months 1-6 post-transplantation | Time to first occurence of a ≥50% decrease in eGFR from baseline during months 1-6 post-transplantation |
| Number of Enterobacterales Urinary Tract Infections | Months 1-6 post-transplantation | Number of Enterobacterales urinary tract infections during months 1-6 post-transplantation |
| Number of All Urinary Tract Infections | Months 1-6 post-transplantation | Number of all urinary tract infections during months 1-6 post-transplantation |
| Number of All Bloodstream Infections | Months 1-6 post-transplantation | Number of all bloodstream infections during months 1-6 post-transplantation |
| Participants Experiencing at Least One Serious Adverse Event and/or Adverse Event of Interest | Months 1-6 post-transplantation | Proportion of participants experiencing at least one serious adverse event and/or at least one adverse event of interest during months 1-6 post-transplantation. |
| Participants Experiencing at Least One Multidrug-Resistant Organism Infection | Months 1-6 post-transplantation | Proportion of participants experiencing at least one multidrug-resistant organism infection during months 1-6 post-transplantation. |
| Number of Multidrug-Resistant Organism Infections | Months 1-6 post-transplantation | Number of multidrug-resistant organism infections during months 1-6 post-transplantation |
| Participants Experiencing at Least One Clostridioides difficile Infection | Months 1-6 post-transplantation | Proportion of participants experiencing at least one Clostridioides difficile infection during months 1-6 post-transplantation |
| Patient-reported quality of life | Months 1-6 post-transplantation | Patient-reported quality of life assessed 6 months post-transplantation using the Quality of Life Instrument for Solid Organ Transplant Recipients (OTSWI; Forsberg et al., 2012). Total scores range from 0 to 160, with lower scores indicating better quality of life |
Countries
Denmark
Contacts
CONTACTSusanne D Poulsen, MD, dr.med.
CONTACTDina L Møller, MD, Ph.d
Outcome results
None listed