Clinical trial NCT05761405: Potentiated Aminoglycosides in Postoperative Urinary Tract Infection Prophylaxis
Official title: Metabolic Potentiation of Aminoglycosides: a Novel Antimicrobial Strategy to Prevent Urinary Tract Infections (UROPOT TRIAL).
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Urinary Tract Infections
Urological System Complication of Procedure
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
Collaborators: name: Ecole Polytechnique Fédérale de Lausanne
name: Insel Gruppe AG, University Hospital Bern
First posted: 2023-03-09
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, multicentre, double-blind
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Infection prophylaxis
timeFrame: 48 hours postoperatively
Secondary outcomes:
measure: Combined microbiological eradication
timeFrame: 6-8 hours post infusion
measure: Sustained microbiological eradication
timeFrame: Up to 2 weeks
measure: Surgical safety outcome
timeFrame: Day 0-14
measure: Pharmacokinetics outcome
timeFrame: Day 0, Day 2, Day 14
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Day 0-Day 14
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: CHUV
Study officials:
affiliation: Centre Hospitalier Universitaire Vaudois
name: Sylvain Meylan
role: PRINCIPAL_INVESTIGATOR
References: