Potentiated Aminoglycosides in Postoperative Urinary Tract Infection Prophylaxis

NCT05761405 | Recruiting Early Phase 1 DMC

• 1 other identifier: 2022-001979
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

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).

Conditions

Urinary Tract Infections; Urological System Complication of Procedure

Outcome Measures

Primary Outcomes (1)

• Infection prophylaxis

  Incidence of postoperative infections within the initial 48 hours postoperatively.

  48 hours postoperatively

Secondary Outcomes (5)

• Combined microbiological eradication

  6-8 hours post infusion

• Sustained microbiological eradication

  Up to 2 weeks

• Surgical safety outcome

  Day 0-14

• Pharmacokinetics outcome

  Day 0, Day 2, Day 14

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  Day 0-Day 14

Study Arms (3)

Ceftriaxone (CRO)

ACTIVE COMPARATOR

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.

Drug: Ceftriaxon

Aminoglycoside (AMK)

ACTIVE COMPARATOR

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

Drug: Amikacin

AminoglycosideLD + Mannitol (AMK1/2 + MAN)

EXPERIMENTAL

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.

Combination Product: mannitol-enhanced aminoglycoside

Interventions

mannitol-enhanced aminoglycoside COMBINATION_PRODUCT

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.

AminoglycosideLD + Mannitol (AMK1/2 + MAN)

Ceftriaxon DRUG

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.

Ceftriaxone (CRO)

Amikacin DRUG

Preselected patients with ureteral stents in situ who are scheduled to undergo endourological ureteral stent manipulation will have routine urine cultures prior to intervention.

Aminoglycoside (AMK)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• Ecole Polytechnique Fédérale de Lausanne: collaborator
• Insel Gruppe AG, University Hospital Bern: collaborator

Study Sites (1)

CHUV

Lausanne, 1011, Switzerland

RECRUITING

Related Publications (1)

• Stritt K, Roth B, Masnada A, Hammann F, Jacot D, Domingos-Pereira S, Crettenand F, Bohner P, Sommer I, Breat E, Sauser J, Derre L, Haschke M, Collins JJ, McKinney J, Meylan S. UROPOT: study protocol for a randomized, double-blind phase I/II trial for metabolism-based potentiation of antimicrobial prophylaxis in the urological tract. Trials. 2024 Oct 15;25(1):682. doi: 10.1186/s13063-024-08526-7.

  PMID: 39407325 DERIVED

MeSH Terms

Conditions

Urinary Tract Infections

Interventions

Ceftriaxone; Amikacin

Condition Hierarchy (Ancestors)

Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Kanamycin; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Sylvain Meylan

  Centre Hospitalier Universitaire Vaudois

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sylvain Meylan, MD-PhD

CONTACT

+41795569418; sylvain.meylan@chuv.ch

Beat Roth, Prof.

CONTACT

+41213142981; beat.roth@chuv.ch

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Randomized, multicentre, double-blind

Study Record Dates

• First Submitted: November 15, 2022
• First Posted: March 9, 2023
• Study Start: January 16, 2024
• Primary Completion: October 15, 2025
• Study Completion: April 15, 2026
• Last Updated: February 8, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

CH (1)