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Potentiated Aminoglycosides in Postoperative Urinary Tract Infection Prophylaxis (UROPOT)

Primary Purpose

Urinary Tract Infections, Urological System Complication of Procedure

Status
Not yet recruiting
Phase
Early Phase 1
Locations
Study Type
Interventional
Intervention
mannitol-enhanced aminoglycoside
Ceftriaxon
Amikacin
Sponsored by
Centre Hospitalier Universitaire Vaudois
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Urinary Tract Infections

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Written informed consent Adults (≥18 years) Ureteral stent in situ Patients scheduled for endourological ureteral manipulations (e.g. endourological stone surgery, ureteral stent exchange) Asymptomatic bacteriuria with strains of E. coli and/or K. pneumoniae sensitive to Ceftriaxone and Amikacin/Aminoglycosides. Exclusion Criteria: Allergy to one of the study drugs Beta-lactams, aminoglycosides or mannitol Pregnant and lactating women Glomerular filtration rate (CKD-EPI eGFR) < 50ml/min / 1,73m2 Hearing impairment Myasthenia gravis or other forms of myoneural disorders Congestive heart failure, Pulmonary edema Intracranial hemorrhage, blood-brain barrier compromise Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial Antibiotic treatment within 14 days prior to randomization Mixed cultures of E. coli and/or K. pneumonia with other bacteria Inability to understand and follow the protocol Inability to give informed consent BMI<20 or >30

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Active Comparator

    Active Comparator

    Experimental

    Arm Label

    Ceftriaxone (CRO)

    Aminoglycoside (AMK)

    AminoglycosideLD + Mannitol (AMK1/2 + MAN)

    Arm Description

    Ceftriaxone infusion. Ceftriaxone is a beta-lactam antibiotic that is the standard-of-care antibiotic for prophylaxis of asymptomatic bacteriuria in Switzerland. The choice of 2000 mg delivered intravenously reflects the general practice.

    Amikacin infusion Amikacin is an aminoglycoside routinely used in Australia (e.g. amikacin, gentamicin) as the standard of care for antibiotic prophylaxis for endourological treatments. It is also used globally for fever in neutropenia in hematological patients. Due to their relatively limited use, aminoglycosides have low resistance rates amongst Enterobacteriaceae. A single dose of 1000mg will be used intravenously

    Amikacin + Mannitol combination The addition of Mannitol enhances bactericidal effect of amikacin in E.coli and K.pneumoniae in animal models and allows for a decrease of amikacin dosing. A single dose of 500mg (low dose or LD - decrease by 50%) systemic amikacin will be used intravenously in combination with 5 grams mannitol delivered intravenously.

    Outcomes

    Primary Outcome Measures

    Infection prophylaxis
    Incidence of postoperative infections within the initial 48 hours postoperatively.

    Secondary Outcome Measures

    Combined microbiological eradication
    anti-biofilm activity as determined by culture of sonicated catheter (CFU/ml) and intraoperative urine culture (CFU/ml)
    Sustained microbiological eradication
    To document eradication of bacteriuria at postoperative day 2 and 14 day by urine culture (CFU/ml)
    Surgical safety outcome
    Postoperative complications
    Pharmacokinetics outcome
    Measurements of maximum urine drug concentrations (Amikacin, Ceftriaxone, Mannitol)
    Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
    Safety and tolerability of Amikacin/Mannitol combination (serious adverse events (SAEs), pre-specified adverse events (AEs) of special interest (ototoxicity, nephrotoxicity).

    Full Information

    First Posted
    November 15, 2022
    Last Updated
    August 28, 2023
    Sponsor
    Centre Hospitalier Universitaire Vaudois
    Collaborators
    Ecole Polytechnique Fédérale de Lausanne, Insel Gruppe AG, University Hospital Bern
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05761405
    Brief Title
    Potentiated Aminoglycosides in Postoperative Urinary Tract Infection Prophylaxis
    Acronym
    UROPOT
    Official Title
    Metabolic Potentiation of Aminoglycosides: a Novel Antimicrobial Strategy to Prevent Urinary Tract Infections (UROPOT TRIAL).
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 16, 2023 (Anticipated)
    Primary Completion Date
    October 15, 2025 (Anticipated)
    Study Completion Date
    April 15, 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Centre Hospitalier Universitaire Vaudois
    Collaborators
    Ecole Polytechnique Fédérale de Lausanne, Insel Gruppe AG, University Hospital Bern

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Urinary tract hardware such as pig-tail catheters are are frequently used for management of urolithiasis or other obstructive pathologies. They are readily colonized by urogenital flora leading to asymptomatic bacteriuria. While asymptomatic bacteriuria is not per se a problem for patients, it may lead to severe infections in the context of hardware manipulation leading to mucosal damage (e.g. catheter exchanges or stone extraction). Such interventions therefore warrant an antibiotic prophylaxis. However, bacteria rapidly form biofilms on hardware; aside of fluoroquinolones, antibiotics have limited anti-biofilm activity. Furthermore, the widespread use of antibiotics has lead to resistant strains. Hence, novel antimicrobial strategies are needed. Recently, metabolism-based potentiation of aminoglycoside has shown high antimicrobial activity against persistent forms of bacteria such as biofilms in the context of murine catheter-associated urinary tract infections. Because of the highly favorable pharmacodynamic profile of aminoglycoside in the urinary tract and the metabolic potentiation, aminoglycosides can be reduced to levels with minimal toxicity. UROPOT aims to compare the efficacy of potentiated aminoglycoside to standard of care for (i) prophylaxis of asymptomatic bacteriuria during urinary hardware manipulations with mucosal trauma (Pig-tail catheter exchange, stone surgery with prior in-dwelling catheter, etc.) and (ii) sustained microbiological eradication through antibiofilm activity. UROPOT will compare the rate of post-interventional urinary tract infections (primary outcome). It will also assess safety and eradication potency (microbiological outcome).
    Detailed Description
    UROPOT is a randomized, single-centre, double-blind, pilot trial comparing a combination of aminoglycosides and mannitol to standard of care or aminoglycosides alone for the peri-operative antimicrobial prophylaxis of endourological procedures with mucosal trauma in the presence of hardware. Adults (≥18 years) scheduled for such procedures with mucosal trauma (stone surgery with hardware, pig-tail catheter exchanges) and having an asymptomatic bacteriuria E. coli or K. pneumoniae as identified 10 days prior to surgery, will be randomly assigned (1:1:1) to receive standard prophylaxis (gen. Ceftriaxone 2 g) for 24 hours, a single dose of amikacin (6mg/kg i.v.) or a single dose of mannitol (pres. 2.5g i.v. bolus)/amikacin (3mg/kg i.v.). Sample size for the three groups will be constructed to demonstrate a non-inferiority for the clinical outcome (absence of infectious complication within 48 hours from operation) with a power of 80%. Complications in the absence of antimicrobial prophylaxis range from 2-10%. Patients will be excluded if baseline urine culture has another bacterial pathogen or E. coli or K. pneumoniae are documented to be aminoglycoside resistant. The primary endpoint will be the prevention of complications(clinical) that will be evaluated for non-inferiority compared to the accepted standard of care. i.e., within a 6% margin Assuming a rate of complication as low as 2%, the new treatments will be considered non-inferior if the corresponding rate of complication is not above 8% (i.e., 6% margin). This non-inferiority margin can be evaluated with a total for 128 patients per treatment arm, at 1-sided alpha of 5%, with power 80%, through an exact two-sample test for proportions. Two comparisons will be performed of arm A and of arm B versus standard of care (SoC). In addition, a microbiological outcome will be included to document higher biofilm eradication rate. This will be documented by sonication of extracted hardware as well as repeat urine culture at post-operative days 7 and 14 days (secondary outcomes). Safety will be monitored with a specific focus on nephrotoxicity and ototoxicity. If highly efficient, this novel antimicrobial strategy would be expanded to treatment of complicated urinary tract infections.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Urinary Tract Infections, Urological System Complication of Procedure

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Early Phase 1
    Interventional Study Model
    Parallel Assignment
    Model Description
    Randomized, multicentre, double-blind
    Masking
    ParticipantCare ProviderInvestigator
    Masking Description
    The pharmacy prepares a randomization list with an additional 20% to account for drop-outs. Based on this, the pharmacy prepares labels (study ID, local center ID, subject ID) and a randomization list (subject ID, open-label treatment (i.e. AMK, AMK+MAN, CRO)). These are delivered to the blinded to the patient awaiting surgery with anonymized subject IDs (consecutive numbering). The investigator has no access to this list.
    Allocation
    Randomized
    Enrollment
    90 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Ceftriaxone (CRO)
    Arm Type
    Active Comparator
    Arm Description
    Ceftriaxone infusion. Ceftriaxone is a beta-lactam antibiotic that is the standard-of-care antibiotic for prophylaxis of asymptomatic bacteriuria in Switzerland. The choice of 2000 mg delivered intravenously reflects the general practice.
    Arm Title
    Aminoglycoside (AMK)
    Arm Type
    Active Comparator
    Arm Description
    Amikacin infusion Amikacin is an aminoglycoside routinely used in Australia (e.g. amikacin, gentamicin) as the standard of care for antibiotic prophylaxis for endourological treatments. It is also used globally for fever in neutropenia in hematological patients. Due to their relatively limited use, aminoglycosides have low resistance rates amongst Enterobacteriaceae. A single dose of 1000mg will be used intravenously
    Arm Title
    AminoglycosideLD + Mannitol (AMK1/2 + MAN)
    Arm Type
    Experimental
    Arm Description
    Amikacin + Mannitol combination The addition of Mannitol enhances bactericidal effect of amikacin in E.coli and K.pneumoniae in animal models and allows for a decrease of amikacin dosing. A single dose of 500mg (low dose or LD - decrease by 50%) systemic amikacin will be used intravenously in combination with 5 grams mannitol delivered intravenously.
    Intervention Type
    Combination Product
    Intervention Name(s)
    mannitol-enhanced aminoglycoside
    Intervention Description
    Preselected patients with ureteral stents in situ who are scheduled to undergo endourological ureteral stent manipulation will have routine urine cultures prior to intervention. Procedures: Consented patients will be randomized for the type of antibiotic prophylaxis according to a global randomization list (i.e. CRO, AMK, AMK1/2+MAN)). Antibiotics (± mannitol) will be delivered in a single infusion that will be administered within 30 minutes.
    Intervention Type
    Drug
    Intervention Name(s)
    Ceftriaxon
    Intervention Description
    Preselected patients with ureteral stents in situ who are scheduled to undergo endourological ureteral stent manipulation will have routine urine cultures prior to intervention. Procedures: Consented patients will be randomized for the type of antibiotic prophylaxis according to a global randomization list (i.e. CRO, AMK, AMK1/2+MAN)). Antibiotics will be delivered in a single infusion that will be administered within 30 minutes.
    Intervention Type
    Drug
    Intervention Name(s)
    Amikacin
    Intervention Description
    Preselected patients with ureteral stents in situ who are scheduled to undergo endourological ureteral stent manipulation will have routine urine cultures prior to intervention.
    Primary Outcome Measure Information:
    Title
    Infection prophylaxis
    Description
    Incidence of postoperative infections within the initial 48 hours postoperatively.
    Time Frame
    48 hours postoperatively
    Secondary Outcome Measure Information:
    Title
    Combined microbiological eradication
    Description
    anti-biofilm activity as determined by culture of sonicated catheter (CFU/ml) and intraoperative urine culture (CFU/ml)
    Time Frame
    6-8 hours post infusion
    Title
    Sustained microbiological eradication
    Description
    To document eradication of bacteriuria at postoperative day 2 and 14 day by urine culture (CFU/ml)
    Time Frame
    Up to 2 weeks
    Title
    Surgical safety outcome
    Description
    Postoperative complications
    Time Frame
    Day 0-14
    Title
    Pharmacokinetics outcome
    Description
    Measurements of maximum urine drug concentrations (Amikacin, Ceftriaxone, Mannitol)
    Time Frame
    Day 0, Day 2, Day 14
    Title
    Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
    Description
    Safety and tolerability of Amikacin/Mannitol combination (serious adverse events (SAEs), pre-specified adverse events (AEs) of special interest (ototoxicity, nephrotoxicity).
    Time Frame
    Day 0-Day 14

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Written informed consent Adults (≥18 years) Ureteral stent in situ Patients scheduled for endourological ureteral manipulations (e.g. endourological stone surgery, ureteral stent exchange) Asymptomatic bacteriuria with strains of E. coli and/or K. pneumoniae sensitive to Ceftriaxone and Amikacin/Aminoglycosides. Exclusion Criteria: Allergy to one of the study drugs Beta-lactams, aminoglycosides or mannitol Pregnant and lactating women Glomerular filtration rate (CKD-EPI eGFR) < 50ml/min / 1,73m2 Hearing impairment Myasthenia gravis or other forms of myoneural disorders Congestive heart failure, Pulmonary edema Intracranial hemorrhage, blood-brain barrier compromise Previous (within 3 months prior to randomization) or concomitant participation in another interventional clinical trial Antibiotic treatment within 14 days prior to randomization Mixed cultures of E. coli and/or K. pneumonia with other bacteria Inability to understand and follow the protocol Inability to give informed consent BMI<20 or >30
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Sylvain Meylan, MD-PhD
    Phone
    +41795569418
    Email
    sylvain.meylan@chuv.ch
    First Name & Middle Initial & Last Name or Official Title & Degree
    Beat Roth, Prof.
    Phone
    +41213142981
    Email
    beat.roth@chuv.ch
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Sylvain Meylan
    Organizational Affiliation
    Centre Hospitalier Universitaire Vaudois
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes

    Learn more about this trial

    Potentiated Aminoglycosides in Postoperative Urinary Tract Infection Prophylaxis

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