Journal Article

Multicentre, open-label, phase IV, randomised trial testing superiority of individualised targeted antibiotic prophylaxis over empiric prophylaxis at ureteral stent removal following cystectomy: study protocol for the REINFORCE trial

Røder, Andreas, Ynddal, Mie Skjøttgaard, Joensen, Ulla Nordström, Vejlgaard, Maja, Stroomberg, Hein Vincent, Moser, Claus

2025

Overview

Background In the first months after cystectomy, the most frequent cause of readmission is infection from the urinary tract. Nonetheless, current guidelines are unable to provide evidence-based recommendations on preventative measures and, as a result, antibiotic prophylaxis varies across surgical centres. Most centres in Denmark administer empiric antibiotic prophylaxis at ureteral stent removal after cystectomy, where infection rates peak. However, data indicates that the postoperative urinary microbiota is composed of a wide range of bacteria, suggesting that the patients may benefit from an individualised approach. This trial aims to test whether targeted postoperative antibiotic prophylaxis can reduce infection-related readmissions after cystectomy compared to the current empiric approach. Methods We present a multicentre, open-label, superiority, randomised clinical trial using a group-sequential design. Participants will be randomly assigned with a 1:1 allocation ratio to receive one of two orally administered single-day antibiotic treatments on the day of ureteral stent removal: (a) standard-of-care pivmecillinam 400 mg morning, noon, and evening or (b) antibiotics targeted to the microbiota identified in a postoperative urine sample. The primary endpoint is the infection-related readmission rate after 90 postoperative days. Secondary endpoints include complication and readmission rates, days alive and out of hospital, quality of life, and microbiological isolates in the urine and blood and antimicrobial susceptibility analyses. A total of 248 patients are planned to be enrolled. The sample size is based on a hypothesised absolute risk reduction in the infection-related readmission rate from 29 to 14%, corresponding to a number needed to treat of six to reduce one hospital readmission. A group-sequential design is proposed to allow for early stopping at interim analysis after 50% enrolment based on predefined rules. Discussion Responsible use of antibiotics is gaining increasing importance globally, and proper prophylactic strategies amongst high-risk patients are essential to avoid hospital admissions with administration of broad-spectrum agents. In this protocol, we present the first randomised clinical trial testing whether individualised targeted antibiotics can reduce the risk of infections after cystectomy. Results of the trial may improve recovery for this vulnerable patient group, while also potentially improving antibiotic stewardship. Trial registration EU trial number 2024–514312-27–00. Registered on December 10, 2024. ClinicalTrials.gov NCT06709196. Registered on November 27, 2024.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Anti-Bacterial Agents - administration & dosage / Antibiotic Prophylaxis - adverse effects / Antibiotic Prophylaxis - methods / Antibiotic stewardship / Antibiotics / Antimicrobial prophylaxis / Biomedicine / Care and treatment / Clinical medicine / Clinical trials / Cystectomy / Cystectomy - adverse effects / Denmark / Device Removal - adverse effects / Disease prevention / Equivalence Trials as Topic / Funding / Health Sciences / Hospitals / Humans / Ileal conduit / Infection control / Informed consent / Intervention / Medical care / Medicine / Medicine & Public Health / Microbiota (Symbiotic organisms) / Multicenter Studies as Topic / Multicentre / Ostomy / Pathogens / Patient Readmission - statistics & numerical data / Pivmecillinam / Postoperative infections / Product development / Prostate / Quality management / Randomized Controlled Trials as Topic / Statistics for Life Sciences / Stent (Surgery) / Stents / Stents - adverse effects / Study Protocol / Surgical clinics / Time Factors / Treatment Outcome / Ureter - surgery / Urinary tract diseases / Urinary tract infections / Urinary Tract Infections - microbiology / Urinary Tract Infections - prevention & control / Urogenital system / Urological surgery / Urology