Prediction and Prevention of Bloodstream Infections After Kidney Transplantation

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.

Inclusion criteria

• Age ≥18 years.
• Kidney transplant recipient.
• Able to provide written informed consent.
• ≥1 urine sample with bacteriuria ≥10^5 CFU/mL (excluding fungi) within first month post-transplantation.

Exclusion criteria

• Known strictures in the esophagus and/or obstructions in the gastrointestinal tract including diabetes gastroparesis.
• Known hypersensitivity or allergy to β-lactam antibiotics.
• Known or suspected genetic metabolism anomalies in the carnitine metabolism, including carnitine transporter defect or organic acidurias such as methylmalonic aciduria or propionic acidaemia.
• Individuals of Faroese descent (defined as both biological parents born in the Faroe Islands).
• Porphyria.
• Current treatment with valproic acid, valproate or other medications liberating pivalic acid.
• Current treatment with probenecid.
• Current treatment with methotrexate.
• Ongoing dialysis one month post-transplantation.
• Pregnancy or breastfeeding.