The effect of gut resistome on the development of antimicrobial resistance in Gram-negative urinary tract infection pathogens: a single center cohort study with kidney transplant recipients

• Applicant: Dr. Ali Kaan Kocer
• Subject Area: Clinical Infectiology and Tropical Medicine ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518875950

The most common infections after kidney transplantation are urinary tract infections (UTIs). The consequences are severe and associated with increased morbidity and hospitalization rates and acute transplantation rejection. An uncomplicated urinary tract infection can rapidly progress to pyelonephritis or urosepsis, which can permanently impair graft function. The most common etiology is Gram-negative bacteria and the increase in antibiotic resistance rates among these pathogens has accelerated dramatically in recent years. Infections with these multidrug-resistant pathogens are associated with poor clinical outcomes due to limited treatment options. In addition, due to frequent exposure to antibiotics (both through prolonged therapy and prophylactic measures), there is a high risk of resistance development. Therefore, rational use of antibiotics in terms of antibiotic therapy selection and duration is in this patient cohort particularly important. Antibiotic resistance can occur both by spontaneous mutation due to increased selection pressure and can be acquired by genetic exchange (e.g., horizontal gene transfer; HGT). The human gut is considered an important reservoir of antimicrobial resistance, and gut bacteria, including Gram-negative UTI-pathogens from the Enterobacterales family, such as E. coli, acquire new antimicrobial resistance genes (ARGs) mainly through horizontal gene transfer. However, it remains unknown whether these bacteria acquire ARGs, which were already present in this gut resistome, and whether these ARGs are detectable in the gut resistome long before the infection. Furthermore, the effects of long-term antibacterial prophylaxis on the gut resistome have been understudied. Innovations in molecular biology such as metagenomic analysis using next-generation sequencing (NGS) provide accurate insights into the resistome by detecting species-independent antimicrobial resistance determinants even from non-pathogenic bacteria and are, therefore, critical for understanding the dynamics of ARG transmission. Clinical studies are needed that address the potential impact of metagenomic sequencing on patient management, including initiation and adaptation of antimicrobials. Against this background, this study aims to investigate the relationship between the gut resistome and the risk of developing bacteriuria or urinary tract infection with multidrug-resistant pathogens using NGS. Furthermore, the microbial evolution of UTI pathogens in recurrent infections and the response of gut resistome to long-term prophylaxis with cotrimoxazole after transplantation will be investigated. New insights from this study may contribute to reducing unnecessary antibiotic use and preventing resistance development by optimizing empiric antibiotic therapy. Curbing the development of resistance in uropathogenic bacteria is in the interest of the individual patient and the community.

• DFG Programme: Research Grants