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

Study Overview
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Brief Summary
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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.

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

Conditions
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Pyelonephritis Acute, Kidney Transplant Infection

Intervention / Treatment
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* Drug: Short antibiotic treatment
* Drug: Usual antibiotic treatment


Participation Criteria
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Eligibility Criteria
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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) 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...) Early response after 48h of antibiotic treatment defined by: T°<38°C and improvement or complete resolution of any symptoms and/or signs of UTI if present at baseline 48 to 60 hours after the first administration of effective antibiotic. Written informed consent Exclusion Criteria: Severe or complicated conditions 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 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) Prior inclusion in this study current participation to another interventional study Neurogenic bladder Enterocystoplasty Immunodeficiency or immunosuppressive therapy not related to kidney transplantation including hematologic malignancy, cancer, asplenia, neutropenia<500 PNN/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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 
| Antibiotic consumption | Antibiotic consumption (indication, dose and duration) throughout the follow-up will be recorded. | at day 180 | 
| Rectal carriage | Rectal carriage of antibiotic resistant bacteria at the end of treatment and at day 14 and day 30 | at day 14 and day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibiotic therapy, duration of antibiotic treatment reduction