Potentiated Aminoglycosides in Postoperative Urinary Tract Infection Prophylaxis

NCT ID: NCT05761405

Last Updated: 2024-02-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-16
• Study Completion Date: 2026-04-15

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.

Conditions

Urinary Tract Infections; Urological System Complication of Procedure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Ceftriaxone (CRO)

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.

Group Type: ACTIVE_COMPARATOR

Ceftriaxon

Intervention Type: 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.

Aminoglycoside (AMK)

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

Group Type: ACTIVE_COMPARATOR

Amikacin

Intervention Type: 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.

AminoglycosideLD + Mannitol (AMK1/2 + MAN)

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.

Group Type: EXPERIMENTAL

mannitol-enhanced aminoglycoside

Intervention Type: 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.

Interventions

mannitol-enhanced aminoglycoside

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: COMBINATION_PRODUCT

Ceftriaxon

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

Amikacin

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

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ecole Polytechnique Fédérale de Lausanne

OTHER

Sponsor Role: collaborator

Insel Gruppe AG, University Hospital Bern

OTHER

Sponsor Role: collaborator

Centre Hospitalier Universitaire Vaudois

OTHER

Sponsor Role: lead

Responsible Party

Sylvain Meylan

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sylvain Meylan

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire Vaudois

Locations

CHUV

Lausanne, , Switzerland

Site Status: RECRUITING

Countries

Switzerland

Central Contacts

Sylvain Meylan, MD-PhD

Role: CONTACT

sylvain.meylan@chuv.ch

+41795569418

Beat Roth, Prof.

Role: CONTACT

beat.roth@chuv.ch

+41213142981

Facility Contacts

Sylvain Meylan, MD-PhD

Role: primary

References

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.

Reference Type: DERIVED

PMID: 39407325 (View on PubMed)

Other Identifiers

2022-001979

Identifier Type: -

Identifier Source: org_study_id