Efficacy of 7 Days Versus 14 Days of Antibiotic Therapy for Acute Pyelonephritis in Kidney Transplant Recipients, a Multicentre Randomized Non-inferiority Trial. (SHORTCUT)

Infections are a major cause of morbidity and mortality in solid organ transplant recipients. In kidney transplant recipients (KTR) urinary tract infection (UTI) represent 45-72% of all infections, and 30% of all hospitalizations for sepsis. Acute transplant pyelonephritis are the most common complications occurring in more than 20% of patients, mainly in the first year after transplantation. They are associated with an increased risk of acute kidney rejection and long-term kidney graft dysfunction. Gram-negative bacteria, mainly E. coli, account for more than 70% of UTI in KTR. As those infections are favoured by urinary tract modifications/defects and immunosuppression, they are often recurrent and necessitate repeated courses of antibiotics. Selective pressure due to antibiotic consumption, along with frequent hospital admissions and immunosuppression, are well known risk factors for the development of antibiotic resistant infections. Multidrug (MDR)- or extensively (XDR)- drug resistant Enterobacteriaceae including ESBL- or carbapenemase-producing organisms, are thus increasingly observed in transplant units and represent a global threat as very few new antibiotics are expected in the next decade.

One main strategy to limit antimicrobial resistance is to reduce the duration of antibiotic treatment. A 7 day-course is recommended for simple acute pyelonephritis (APN) treated with fluoroquinolones or parenteral B-lactams, prolonged up to 10 or 14 days in the presence of underlying disease at risk of complications. Most KT teams treat patients between 14-21 days as recommended by American guidelines. However, the need to extend treatment duration in immunosuppressed patients is a poorly defined concept and the optimal duration of treatment for APN in KTR is not known as these patients are excluded from most studies.

As there is an urgent need to reduce antibiotic consumption in this population at high risk of developing infections due to resistant pathogens, the hypothesis is that a 7 day-treatment is sufficient to cure APN with good clinical response after 48h of treatment in KTR and is as effective as 14 days.

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplant Infection; Pyelonephritis Acute
• Intervention / Treatment: Drug: Short antibiotic treatment; Drug: Usual antibiotic treatment

• Study Type: Interventional
• Enrollment (Estimated): 470
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: matthieu resche-rigon, MDPHD; Phone Number: +33 142499742; Email: matthieu.resche-rigon@u-paris.fr
• Study Contact Backup: Name: Matthieu Lafaurie, MD; Phone Number: +33 142494117; Email: matthieu.lafaurie@aphp.fr

Study Locations

• France
  • Bordeaux, France
    • Not yet recruiting
    • CHU Bordeaux
    • Contact: Hannah Kaminski, Dr
  • Boulogne-Billancourt, France
    • Not yet recruiting
    • Hopital Foch
    • Contact: Michel Delahousse, Dr
  • Créteil, France
    • Not yet recruiting
    • CHU Mondor
    • Contact: Marie Matignon, Dr
  • Lille, France
    • Not yet recruiting
    • CHRU Lille
    • Contact: Marc Hazzan, Pr
  • Lyon, France
    • Not yet recruiting
    • CHU Lyon
    • Contact: Charlene Levi, Dr
  • Nantes, France
    • Not yet recruiting
    • CHU Nantes
    • Contact: Clément Deltombe, Dr
  • Paris, France
    • Recruiting
    • CHU Saint Louis
    • Contact: Gillian Divard, Dr
  • Paris, France
    • Not yet recruiting
    • CHU Kremlin-Bicêtre
    • Contact: Renaud Snanoudj, Pr
  • Paris, France
    • Not yet recruiting
    • CHU Necker
    • Contact: Carole Burger, Dr
  • Toulouse, France
    • Not yet recruiting
    • CHU Toulouse
    • Contact: Nassim Kamar, Pr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >18 years KTR
• APN defined by: fever (T°≥38°C) (with or without clinical signs and/or symptoms of UTI) and pyuria (≥10^4 white blood cells/mL or ≥10/mm3) and positive urine culture (single uropathogen ≥10^3 CFU/mL susceptible to the empirically administrated antibiotic)
• No confirmed or suspected febrile non urinary bacterial infection
• No urologic/renal complication at baseline imaging (abscess, obstruction...)
• Favourable early response to antibiotic treatment:( 48 to 60 hours after the first dose of antibiotic effective against the causative uropathogen) defined by: T°<38°C and improvement (or resolution) of signs and/or symptoms of urinary tract infection if present at diagnosis
• Written informed consent

Exclusion Criteria:

• Severe or complicated condition

  • Any rapidly progressing disease or immediately life-threatening illness, including, but not limited to, septic shock, current or impeding respiratory failure, acute heart or liver failure
  • Admission or stay in intensive care unit at baseline
  • Obstruction of the urinary tract
  • Renal, perinephric or prostatic abscess
• Prior inclusion in this study
• Current participation to another interventional study
• Dual antibiotic therapy (prophylactic antibiotic such as cotrimoxazole allowed) (only 1 dose of aminoside is allowed before randomization)
• First month post transplantation
• Current indwelling catheter (including bladder catheter, ureteral stents, percutaneous nephrostomy tubes)
• Neurogenic bladder
• Enterocystoplasty
• Immunodeficiency or immunosuppressive therapy not related to kidney transplantation including hematologic malignancy, cancer, asplenia, neutropenia<500 neutrophils/mm3
• Pregnancy, breastfeeding
• Hypersensitivity or previous severe adverse drug reaction to the antibiotic therapy
• Unable or unwilling, in the judgment of the investigator, to comply with the protocol
• Life expectancy<1 month
• Patient under legal guardianship or without healthcare coverage
• Homeless patient
• Women with childbearing potential not using adequate contraception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 7 day-duration antibiotic treatment	Drug: Short antibiotic treatment; 7 day-duration antibiotic treatment. The choice of antibiotic treatment is left to the medical team in charge of the patient.
Active Comparator: 14 day-duration antibiotic treatment	Drug: Usual antibiotic treatment; 14 day-duration antibiotic treatment. The choice of antibiotic treatment is left to the medical team in charge of the patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure day 30	Clinical cure and microbiological eradication and no additional antibiotic treatment since the end of antibiotic treatment up to the main evaluation at day 30. Clinical cure is defined as fever <38°C and no symptoms of Urinary Tract Infection (UTI). Microbiological eradication is defined as uropathogen ≤ 10.3 CFU/mL in urine culture.	at day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical cure day 90	Clinical cure and microbiological eradication and no additional antibiotic treatment since the end of antibiotic treatment up to the main evaluation at day 90. Clinical cure is defined as fever <38°C and no symptoms of Urinary Tract Infection (UTI). Microbiological eradication is defined as uropathogen ≤ 10.3 CFU/mL in urine culture.	at day 90
Clinical cure day 180	Clinical cure and microbiological eradication and no additional antibiotic treatment since the end of antibiotic treatment up to the main evaluation at day 180. Clinical cure is defined as fever <38°C and no symptoms of Urinary Tract Infection (UTI). Microbiological eradication is defined as uropathogen ≤ 10.3 CFU/mL in urine culture.	at day 180
Incidence of relapse/recurrence day 30	Relapse or recurrence of the Urinary Tract Infection	at day 30
Incidence of relapse/recurrence day 90	Relapse or recurrence of the Urinary Tract Infection	at day 90
Incidence of adverse event	Incidence of adverse events imputable to antibiotic treatment	at day 180
MDRD	Modification of Diet in Renal Disease (MDRD) Study equation. Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol 2005;16(3):763-73.	at day 90 and day 180
CKD	CKD-EPI (Chronic Kidney Disease EPIdemiology collaboration, Levey, 2009) A New Equation to Estimate Glomerular Filtration Rate. Andrew S. Levey, MD; Lesley A. Stevens, MD, MS; Christopher H. Schmid, PhD; Yaping (Lucy) Zhang, MS; Alejandro F. Castro III, MPH; Harold I. Feldman, MD, MSCE; John W. Kusek, PhD; Paul Eggers, PhD; Frederick Van Lente, PhD; Tom Greene, PhD; and Josef Coresh, MD, PhD, MHS, for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). Annals of Internal Medicine 2009;150(9):604-613	at day 90 and day 180
Hospital length of stay	Hospitalisation length stay defined by the delay between the date of inclusion and the date of hospital discharge	at day 180
Microbiological cure day 30	Microbiological cure is defined as a sterile urine or uropathogene ≤ 103 CFU/mL in urine culture	at day 30
Microbiological cure day 90	Microbiological cure is defined as a sterile urine or uropathogene ≤ 103 CFU/mL in urine culture	at day 90
Microbiological cure day 180	Microbiological cure is defined as a sterile urine or uropathogene ≤ 103 CFU/mL in urine culture	at day 180
MDRD	Modification of Diet in Renal Disease (MDRD) Study equation. Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol 2005;16(3):763-73.	at day 180
CKD	CKD-EPI (Chronic Kidney Disease EPIdemiology collaboration, Levey, 2009) A New Equation to Estimate Glomerular Filtration Rate. Andrew S. Levey, MD; Lesley A. Stevens, MD, MS; Christopher H. Schmid, PhD; Yaping (Lucy) Zhang, MS; Alejandro F. Castro III, MPH; Harold I. Feldman, MD, MSCE; John W. Kusek, PhD; Paul Eggers, PhD; Frederick Van Lente, PhD; Tom Greene, PhD; and Josef Coresh, MD, PhD, MHS, for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). Annals of Internal Medicine 2009;150(9):604-613	at day 180
Antibiotic consumption	Antibiotic consumption (indication, dose and duration) throughout the follow-up will be recorded.	Up to day 180
Rectal carriage	Rectal carriage of antibiotic resistant Enterobacteriaceae	at inclusion
Rectal carriage	Rectal carriage of antibiotic resistant Enterobacteriaceae	at day 30

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2024
• Primary Completion (Estimated): March 22, 2027
• Study Completion (Estimated): August 22, 2027

Study Registration Dates

• First Submitted: October 24, 2022
• First Submitted That Met QC Criteria: October 24, 2022
• First Posted (Actual): October 28, 2022

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: antibiotic therapy; duration of antibiotic treatment reduction
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Nephritis; Nephritis, Interstitial; Pyelitis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pyelonephritis; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: APHP200020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No