New DEEP-URO study builds on GPIU success

It’s time to find a solution for antimicrobial-resistant bacteria

international offices, and pharmaceutical companies. Our goal was to design and develop a dynamic Pan-European scientific platform, capable of connecting and operating many independent, integrative modules. We aimed to create a global network for infectious disease research and patient care, with UTI serving as the pilot specialty of the platform (Figure 3a, 3b, and 4).

(GB), Prof. Tommaso Cai (IT), Prof. Florian Wagenlehner (DE), Dr. Béla Köves (HU), Prof. Kurt Naber (DE)

Over the past 20 years we have been conducting the Global Prevalence Study of Infections in Urology (GPIU), which has allowed us to identify the increasing threat of antimicrobial-resistant (AMR) bacteria. This has been a collective effort with the support of the urology community. We are proud to have established a unique position to demonstrate the problem of AMR in urology, and we have been successful in raising awareness of the issue through our research and publications.

However, we know that this is not enough. With the increasing threat of AMR, we need to take action to find a solution. That's why we are embarking on a new journey with the DEEP-URO study, where we aim to evaluate the effectiveness of de-escalation of antibiotic prophylaxis in reducing the incidence of infectious complications and antibiotic resistance while maintaining patient safety. We are confident that with our established collective altruistic approach, we can contribute to tackling AMR in urology, and our efforts will contribute worldwide (Figure 1).

Nonetheless, we persevered, and the first annual registration was conducted in 2003. It was christened the Pan European Prevalence study (PEP-study). The registration process proved to be a resounding success, and the study was repeated the following year as the Pan Euro-Asian Prevalence study (PEAP-study).

The success of the study continued, and it evolved into GPIU, the Global Prevalence study on Infections in Urology. By 2015, the study was operational in 73 countries, and over the years, more than 30,000 hospitalised urological patients have been screened for hospital-acquired infections. [1] retrospective data analyses published and to influence guidelines recommendations. We were criticised for a continuous retrospective approach and for random inclusion of study centres over the years. Not even the best mathematical modelling could compensate for that. We could also not provide evidence that local investigators had been trained to fill in report forms. Although the study always had a central ethical approval, hospitals in some countries questioned the need for approval by local and regional ethical committees.

After careful consideration, we realised that we were at a crossroads. The success of our SENTRII project had put us in a favourable position to secure funding for several years. However, we were faced with a crucial decision: should we continue with a more educational and developmental project, or shift our focus to a more urology-centric research project that would address the pressing challenges of antibiotic resistance? After much discussion, we decided to pursue a new concept called DEEP-URO (DEEscalation of antibiotic Prophylaxis in UROlogical procedures for prevention/tackling of antibiotic resistance). By leveraging our experience with GPIU, the shortcomings we had encountered, and the new ideas we had developed for SENTRII, we believed that we could make a meaningful contribution to the field of urology and tackle one of the most pressing public health challenges of our time.

In 2021, a dedicated research group was formed with a vision to provide evidence-based answers to all relevant knowledge gaps in the field of genitourinary tract infections that have real-life impact on patients. The group adopted a very focused, management oriented working structure to effectively identify, design, organise and implement multiple research projects. We realised that antibiotic prophylaxis was a field where lack of evidence hinders our ability to provide the best practice to our patients in urology.

DEEP-URO study

The PEP, PEAP and GPIU studies

It all began with Dr. Paul Madsen (DK), who journeyed to Wisconsin with his German spouse in pursuit of their American aspirations. As a result of his contributions to medicine, he was bestowed an honorary degree by the Danish Queen. Dr. Madsen initiated a program of one-year fellowships in urology for talented and driven young urologists. Among the Danes in this group was a German man named Prof. Naber, who was introduced to the study of urinary tract infections. At the EAU congress in Paris in 1996, Prof. Kurt Naber assembled a group of experts from around the world to discuss the pressing issues surrounding UTIs and antibiotic treatment in urology. Invitees included luminaries like Dr. Joan Palou Redorta (ES), Prof. Bernard Lobel (FR), Prof. Henry Botto (FR), Prof. Michael Bishop (UK), Prof. Péter Tenke (HU), Prof. Hakki Mete Cek (TR), and Prof. Bjerklund Johansen. At that time, many of us were unfamiliar with terms such as pharmacokinetics, pharmacodynamics and nosocomial. In 2000, we founded the European Society for Infections in Urology and produced the inaugural edition of the EAU guidelines on UTI. The society later became a full section of the EAU.

Background

It was clear to us that infective complications could pose a significant threat to the success of surgeries. One of the most prevalent diseases we encountered was urinary tract infection (UTI). It became evident that reducing infective complications could serve as a vital tool in improving the quality of care we provided. However, the rate of infective complications in urology, the causative agents, and risk factors were not well understood.

We proposed establishing a prevalence registry through an electronic network like the recently established virtual Institute of Urology in Norway. Prof. Bishop voiced his scepticism, stating that this was not possible on an international level.

Funding and technology

From the beginning, the ESIU and its UTI guidelines panel have faced challenges in finding sponsors due to our unique stance of trying to reduce overconsumption of antibiotics. Nevertheless, we have had the full support of the EAU, EAU Research Foundation, and its secretary generals. Urologists drafted the CRFs and IT structure, and IT engineers at the EAU developed the applications. The study platform relocated to the Technische Hochschule in Mittelhessen (THM) in Giessen, Germany, with more IT support available as the study expanded. Annual grants from the Swiss Merian Iselin Clinic and the invaluable contributions of Prof. Gernot Bonkat (CH) facilitated this relocation.

Outcomes

The PEP and PEAP studies provided crucial insights into hospital acquired infections in urology, including microorganisms causing these infections and their resistance rates to commonly used antibiotics. Over the years, the annual studies have yielded an abundance of data, which has been instrumental in enhancing our understanding of UTI. With these data, we have developed a new clinical classification of UTI, defined contamination categories, identified risk factors, established antibiotic stewardship measures, and informed guidelines on treatment and prophylaxis. Furthermore, several side studies have been performed, including infective complications after prostate biopsies [2] and the SERPENS study on urosepsis which provided valuable data from nearly 1000 patients. The GPIU project has produced numerous lectures, abstracts, articles and doctoral theses, culminating in the ICUD book and the Living textbook, both serving as living monuments of our efforts [3,4]. Most recently, GPIU data was utilised to develop an optimal empirical treatment model for UTI through Bayesian mathematics [5].

The transition

As medical journals and guideline developers came to pay increasing attention to study design and level of evidence, it became more difficult to get our

Meanwhile, nosocomial infections and antimicrobial resistance was increasing and there were few, if any new antibiotics in the pipelines of pharmaceutical companies. The trends we had been studying, the needs we had identified and the measures we had called for were named by others as “antimicrobial stewardship” [6]. A comprehensive evaluation performed on assignment by the UK government told us that our topic was at the heart of an imminent crisis (The O`Neil report). We realised that our experience was valuable but also that we needed to re-define our goals and our way of working. Several meetings were held in the core study group (Figure 2).

With great enthusiasm and determination, we embarked on a months-long journey to develop an application for the EU cost project, SENTRII. This project was nothing short of ambitious, with the support of numerous esteemed researchers, research institutions, scientific organisations,

In the world of medicine, overuse of antibiotics in surgical prophylaxis is a serious issue that contributes to the growing problem of antimicrobial resistance. This can lead to difficulty in treating even the most basic infections after surgery. That's why the DEEP-URO study is so important. It aims to increase our understanding of rates and risk factors for infectious complications in urology and to determine the actual need for antibiotic prophylaxis in urological procedures.

The traditional study designs used in medicine may not be the most efficient way to generate the necessary evidence due to the many technical variations in surgical procedures, patient factors, available antibiotics, and spatiotemporal variation of antimicrobial resistance. That's why the DEEP-URO study has a novel design to generate high-level evidence for appropriate use of antibiotic prophylaxis in urology.

By evaluating the effectiveness and necessity of antibiotic prophylaxis de-escalation for select urological interventions, the DEEP-URO study offers a new approach to solving this critical problem. The study design is summarised in Figure 5.

DEEP-URO will use an innovative study platform that has the potential to improve the use of antibiotics related to urological interventions, thereby leading to better patient outcomes and reduced risk of antibiotic resistance. The platform provides a master protocol with inbuilt study control mechanisms for governance, ethics, common outcome measures and generic confounders.

Study strategy and objectives specific variables. The process of cycles to integrate a surveillance driven RCT approach is illustrated in Figure 6.

DEEP-URO will initially focus on five index procedures, including radical prostatectomy, radical cystectomy, radical nephrectomy, transurethral resection of bladder tumours (TURBT), and transurethral resection of prostate (TURP). Study outcomes will be used to model personalised antibiotic prophylaxis protocols.

The primary objective of DEEP-URO is to identify the limits of antibiotic prophylaxis de-escalation by comparing 30-day infection rates (deep tissue, skin, urinary tract, and sepsis) relative to contemporary intensive antibiotic prophylaxis protocols. Secondary objectives are to measure the need for additional surgical interventions to resolve an infection in 30 days, measure HRQoL (health-related quality of life) outcomes, and establish a separate cohort of microbiological samples of perineal swabs, rectal swabs, and urine for antimicrobial resistome research.

Randomised trial. Run as a step-wedge design, the time a cluster switches from conventional extensive antibiotic prophylaxis arms to the limited antibiotic protocol will be randomised. Each cluster will focus on a specific urological intervention and will be conducted using a stepwise randomisation approach. The study will evaluate the effectiveness of de-escalation of antibiotic prophylaxis in reducing the incidence of infectious complications and antibiotic resistance while maintaining patient safety.

Study sites and time plan

DEEP-URO will be conducted at select hospitals with a well-established track record of successfully recruiting participants in previous portfolio studies, including GPIU and SERPENS. To ensure maximum recruitment, the national representatives should also identify centres in their respective countries that have experience and are skilled at leading capable participant recruitment.

Based on our projections, we estimate that the first cycle of DEEP-URO will take approximately 30 months to complete. However, we anticipate that subsequent cycles will require less time to complete as the knowledge and expertise gained from each cycle accumulates. This will enable us to conduct future cycles more efficiently, potentially reducing the duration of each cycle and accelerating the overall progress of the study.

Organisation

The Deep-URO study is organised with principal investigators, a scientific working group and national lead investigators as shown in Textbox 1.

Principal investigators: Dr. Zafer Tandoğdu (GB), Prof. Florian Wagenlehner (DE), Prof. Truls Erik Bjerklund Johansen (NO)

Study cycles. To achieve study objectives, DEEP-URO will consist of cycles which include a cohort to establish baseline event rates (including AMR rates) followed by a randomised study testing efficacy of de-escalation as compared to standard of care. By following this cyclic structure, the study can be conducted in a rigorous and systematic way, with each cycle building upon the previous one to enhance the effectiveness of antibiotic prophylaxis de-escalation in the context of urological interventions.

Cohort study. The aim is to identify the local incidence of surgical site infections, healthcare associated UTIs and sepsis, as well as antibiotic resistance rates. This information will inform the power calculations of the subsequent cluster randomised trial, which will evaluate the efficacy and safety of antibiotic prophylaxis de-escalation for a select intervention.

Study clusters. Clusters will be created according to local antimicrobial resistance prevalence. The study platform will provide an information governance framework, data collection interface and data storage accessible for all sub-studies within DEEP-URO. A generic case report form (CRF) will be developed with subsections for the index procedure-

Scientific working group: Dr. Lailla Schneidewind (DE), Dr. Jose Medina Polo (ES), Ms. Ana-Maria Tapia (ES), Dr. Jennifer Kranz (DE), Dr. Tommaso Cai (IT), Dr. Béla Köves (HU)

National chief investigators:

• Dr. Jose Medina Polo (ES)

• Prof. Bhaskar Somani (GB)

• Dr. Razvan Petca (RO)

• Dr. Carlos Ferreira, and Dr. Tiago Oliveira (PT)

• Dr. Ulanbek Zhanbyrbekuly (KZ)

• Dr. Akis Afoko (UG)

• Prof. Laila Schneidewind (DE)

• Dr. Maxime Valee (FR)

• Prof. Mathew Roberts (AU)

• Prof. Jørgen Bjerggaard Jensen (DK)

Database administrator: Dr. Adamos Hadjivasiliou (GB)

Research fellow: Dr. Eva Falkensammer (AT)

Textbox 1. Organisation of the DEEP-URO study

DEEP-URO was set in motion at EAU23 in Milan, where study protocols and objectives were discussed. Our scientific working group is committed to identifying the initial index procedures and developing electronic clinical record forms, building on previous work and leveraging IT solutions from the GPIU platform.

We've already conducted a review of infection rates after urological procedures and are currently performing a systematic review of infective complications after robotic-assisted radical prostatectomy. We've scheduled regular video meetings under the leadership of Dr. Köves to ensure everyone is aligned and progressing towards our goals.

Invitation

We invite you to join us on this new journey. Our team values the contributions of all investigators, and we prioritise recognition through co-authorship and acknowledgements. Together, we can make a historical change and find a solution to this growing problem. The DEEP-URO study will soon be open, and we need dedicated investigators and partners from strong urology centres who can commit themselves to perform complete DEEP-URO study cycles for a given procedure and help provide high-level evidence to support publication in high impact journals and inform urological guidelines.

We need investigators who understand the trifecta of antimicrobial stewardship in urology, which can be summarised as "no infections, no resistance, and as little use of antibiotics as possible." Join us in this effort to tackle AMR in urology and make a real difference for patients around the world!

References

1. Wagenlehner F, Tandogdu Z, Bartoletti R et al. The Global Prevalence of Infections in Urology Study: A long term, worldwide surveillance study on urological infections. Pathogens 2016, 19;5(1), 10, doi:10.3390. PMID: 26797640

2. Naber KG, Scaeffer AJ, Heyns CF et al. Urogenital infections (Textbook 1182pp). International Consultation on Urological Diseases (ICUD) and European Association of Urology ISBN: 978-90-79754-41-0, Arnhem: 2010

3. Bjerklund Johansen TE, Wagenlehner FME, Matsumoto T, et al eds. Urogenital infections and inflammations. Berlin: GMS; 2017-.DOI: 10.5680/lhuii000032

4. F.M.E. Wagenlehner, E. van Oostrum, P. Tenke et al. Infective complications after prostate biopsy: Outcome of the Global Prevalence of Infections in Urology (GPIU) prostate biopsy study 2010 and 2011 – A prospective, multinational, multicentre prostate biopsy study. European Urology 2013; 63: 521-527.

5. Zafer Tandoğdu. Healthcare associated urinary tract infections in urology departments. Faculty of Medicine, University of Oslo. 2020. ISBN 978-82-8377-595-2

6. Tommaso Cai. Aspects of antimicrobial stewardship in urinary tract infections. Faculty of Medicine, University of Oslo. ISBN 978-82-8377-941-7