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

Kidney Transplant Infection Clinical Trial

— SHORTCUT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05597540
• Other study ID #: APHP200020
• Status: Recruiting
• Phase: Phase 3
• Start date: February 22, 2024
• Est. completion date: August 22, 2027

Study information

• Verified date: February 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Matthieu Lafaurie, MD
• Phone: 142494117
• Email: matthieu.lafaurie[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 470
• Est. completion date: August 22, 2027
• Est. primary completion date: March 22, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Kidney Transplant Infection
• Pyelonephritis
• Pyelonephritis Acute

Intervention

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.
• Usual antibiotic treatment
14 day-duration antibiotic treatment. The choice of antibiotic treatment is left to the medical team in charge of the patient.

Locations

Country	Name	City	State
France	CHU Bordeaux	Bordeaux
France	Hôpital Foch	Boulogne-Billancourt
France	CHU Mondor	Créteil
France	CHRU Lille	Lille
France	CHU Lyon	Lyon
France	CHU Nantes	Nantes
France	CHU Kremlin-Bicêtre	Paris
France	CHU Necker	Paris
France	CHU Saint Louis	Paris
France	CHU Toulouse	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Microbiological cure day 30	Microbiological cure is defined as a sterile urine or uropathogene = 103 CFU/mL in urine culture	at day 30
Secondary	Microbiological cure day 90	Microbiological cure is defined as a sterile urine or uropathogene = 103 CFU/mL in urine culture	at day 90
Secondary	Microbiological cure day 180	Microbiological cure is defined as a sterile urine or uropathogene = 103 CFU/mL in urine culture	at day 180
Secondary	Incidence of relapse/recurrence day 30	Relapse or recurrence of the Urinary Tract Infection	at day 30
Secondary	Incidence of relapse/recurrence day 90	Relapse or recurrence of the Urinary Tract Infection	at day 90
Secondary	Incidence of adverse event	Incidence of adverse events imputable to antibiotic treatment	at day 180
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Antibiotic consumption	Antibiotic consumption (indication, dose and duration) throughout the follow-up will be recorded.	Up to day 180
Secondary	Rectal carriage	Rectal carriage of antibiotic resistant Enterobacteriaceae	at inclusion
Secondary	Rectal carriage	Rectal carriage of antibiotic resistant Enterobacteriaceae	at day 30