Prediction and Prevention of Bloodstream Infections After Kidney Transplantation

Официальное название

Prediction and Prevention of Bloodstream Infections After Kidney Transplantation - The PREDICT Study

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Pivmecillinam
  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).
• Препарат Placebo
  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.

Первичные конечные точки

• Enterobacterales Urinary Tract Infections and/or Enterobacterales Bloodstream Infections [Срок оценки: Months 1-6 post-transplantation]

Вторичные конечные точки (12)

• Time to Enterobacterales Bloodstream Infection [Срок оценки: Months 1-6 post-transplantation]
• Time to All-Cause Mortality [Срок оценки: Months 1-6 post-transplantation]
• Time to First Hospital Admission [Срок оценки: Months 1-6 post-transplantation]
• Time to Graft Loss [Срок оценки: Months 1-6 post-transplantation]
• Time to ≥50% Decrease in eGFR From Baseline [Срок оценки: Months 1-6 post-transplantation]
• Number of Enterobacterales Urinary Tract Infections [Срок оценки: Months 1-6 post-transplantation]
• Number of All Urinary Tract Infections [Срок оценки: Months 1-6 post-transplantation]
• Number of All Bloodstream Infections [Срок оценки: Months 1-6 post-transplantation]
• Participants Experiencing at Least One Serious Adverse Event and/or Adverse Event of Interest [Срок оценки: Months 1-6 post-transplantation]
• Participants Experiencing at Least One Multidrug-Resistant Organism Infection [Срок оценки: Months 1-6 post-transplantation]
• Number of Multidrug-Resistant Organism Infections [Срок оценки: Months 1-6 post-transplantation]
• Participants Experiencing at Least One Clostridioides difficile Infection [Срок оценки: Months 1-6 post-transplantation]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Дания · 3 центра

• Aarhus University Hospital, Department of Nephrology — Aarhus
• Rigshospitalet, Department of Nephrology — Copenhagen
• Odense University Hospital, Department of Nephrology — Odense

Публикации

• Gondos A, Dohler B, Brenner H, Opelz G. Kidney graft survival in Europe and the United States: strikingly different long-term outcomes. Transplantation. 2013 Jan 27;95(2):267-74. doi: 10.1097/TP.0b013e3182708ea8. PMID 23060279
• Rasmussen DB, Moller DL, Hamm SR, Borges AH, Nielsen ACY, Kirkby NS, Sorensen SS, Nielsen SD. BKPyV DNAemia in Kidney Transplant Recipients Undergoing Regular Screening: A Single-Centre Cohort Study. Microorganisms. 2023 Dec 29;12(1):65. doi: 10.3390/microorganisms12010065. PMID 38257892
• Forsberg A, Persson LO, Nilsson M, Lennerling A. The organ transplant symptom and well-being instrument - psychometric evaluation. Open Nurs J. 2012;6:30-40. doi: 10.2174/1874434601206010030. Epub 2012 Apr 2. PMID 22523527
• Pinart M, Kranz J, Jensen K, Proctor T, Naber K, Kunath F, Wagenlehner F, Schmidt S. Optimal dosage and duration of pivmecillinam treatment for uncomplicated lower urinary tract infections: a systematic review and meta-analysis. Int J Infect Dis. 2017 May;58:96-109. doi: 10.1016/j.ijid.2017.03.012. Epub 2017 Mar 21. PMID 28341436
• Kim DK, Kim JH, Lee JY, Ku NS, Lee HS, Park JY, Kim JW, Kim KJ, Cho KS. Reappraisal of the treatment duration of antibiotic regimens for acute uncomplicated cystitis in adult women: a systematic review and network meta-analysis of 61 randomised clinical trials. Lancet Infect Dis. 2020 Sep;20(9):1080-1088. doi: 10.1016/S1473-3099(20)30121-3. Epub 2020 May 21. PMID 32446327
• Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and th PMID 21292654
• Kranz J, Bartoletti R, Bruyere F, Cai T, Geerlings S, Koves B, Schubert S, Pilatz A, Veeratterapillay R, Wagenlehner FME, Bausch K, Devlies W, Horvath J, Leitner L, Mantica G, Mezei T, Smith EJ, Bonkat G. European Association of Urology Guidelines on Urological Infections: Summary of the 2024 Guidelines. Eur Urol. 2024 Jul;86(1):27-41. doi: 10.1016/j.eururo.2024.03.035. Epub 2024 May 6. PMID 38714379
• Kaye KS, Santerre Henriksen A, Sommer M, Frimodt-Moller N. Safety and Tolerability of Pivmecillinam During More Than Four Decades of Clinical Experience: A Systematic Review. Clin Infect Dis. 2025 Feb 24;80(2):280-299. doi: 10.1093/cid/ciae621. PMID 39835818

Идентификаторы

NCT: NCT07407673 · PREDICT, EU 2026-527337-63-00 · 2026-527337-63-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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