BERKELEY, CA (UroToday.com) - A patient undergoing urinary catheterization has a 3 to 7% risk each day of developing a urinary tract infection (UTI). Catheter-associated UTIs (CAUTIs) are the most common type of nosocomial UTIs and are often caused by multidrug resistant pathogens.
| "This report provides important insights into the mechanisms underlying UPEC-mediated CAUTI in the murine model and informs efforts to design better therapeutic approaches to potentially prevent and treat these infections in humans." |
As a result, CAUTIs are often difficult and expensive to treat. Since in many instances urinary catheterization is a necessary procedure, a better understanding of the mechanisms associated with CAUTI are needed in order to direct development of new therapeutics. A new report from the laboratory of Scott Hultgren at Washington University in St Louis uncovers novel aspects of CAUTIs using a murine model of foreign body-associated UTI recently optimized in the laboratory to closely mimic CAUTI. Uropathogenic Escherichia coli (UPEC) is the major cause of all UTIs, including CAUTI. Hultgren and others have previously shown in animal models that during acute infections of the bladder, UPEC elaborates an adhesive fiber, type 1 pili, which promotes adhesion to and invasion of superficial bladder epithelial cells. Once intracellular, UPEC can form a dense intracellular bacterial community (IBC), a process that also requires type 1 pili. A clinical study performed in collaboration with Dr. Thomas Hooton in Seattle provided evidence that this IBC pathway may also occur in humans, a finding that might help explain many of the recurrent UTIs afflicting women.
The results from more recent studies by Hultgren using the murine model, published in Antimicrobial Agents and Chemotherapy, revealed that during a CAUTI, UPEC is also able to bind to and invade bladder cells and that type 1 pili promotes the formation of biofilms on implanted catheter material. The formation of IBCs in the context of urinary catheterization, if reflective of UTI pathogenesis in humans, has important ramifications in the clinical management of UTIs. One consequence of IBC formation is the development of quiescent intracellular reservoirs (QIRs), which are posited to be one possible origin of recurrent UTIs. The current report suggests that these pre-existing intracellular bacterial reservoirs from previous UTIs can resurface and serve as a nidus for catheter colonization. If this scenario occurs in humans, findings from this study suggest that patients with a history of UTIs who are catheterized may be at greater risk of subsequent CAUTI. The risk of UTI may persist even after catheter removal due to QIRs. These studies highlight the need for more investigations into the mechanisms of CAUTI and its consequences.
The ever-increasing prevalence of antimicrobial resistance, especially within biofilms, underscores the need for better preventative and therapeutic approaches to CAUTI. To that end, Hultgren and colleagues propose the use of small molecule inhibitors of type 1 pili, called mannosides, to prevent and treat CAUTI. Working in collaboration with Janetka, the team utilized rational structure-based drug design to develop novel tight-binding biaryl mannosides which potently block the interaction between the tip adhesin of type 1 pili and glycosylated residues on the uroepithelial surface. Mannosides prevent IBC formation and UTI in a murine model of ascending UTI. Now the authors find that type 1 pili are also required for IBC formation and catheter colonization during UPEC CAUTIs. Furthermore, combination therapy with mannosides and antibiotics can prevent UPEC CAUTI. Mannoside treatment did not disrupt previously established CAUTI, but the authors suggest that further optimization of the murine model, as well as the mannosides, will help achieve this goal. This report provides important insights into the mechanisms underlying UPEC-mediated CAUTI in the murine model and informs efforts to design better therapeutic approaches to potentially prevent and treat these infections in humans. Targeting type 1 pili is just the tip of the iceberg as UPEC has an arsenal of virulence factors to mediate infection and thus further research is warranted to identify other biofilm and virulence determinants of UPEC CAUTI as well as host factors, which can serve as biomarkers and antimicrobial targets in the prevention, diagnosis, and treatment of CAUTI.
Written by:
Matthew R. Chapman, PhD1 and Thomas M. Hooton, MD2 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
1Department of Molecular, Cellular, and Developmental Biology
University of Michigan
830 North University
Ann Arbor, MI 48109 U.S.A.
(734) 764-7592 PH
(734) 647-0884 Fax
2Department of Medicine
University of Miami School of Medicine
Miami, FL 33136 USA
(305) 243 2576 PH
(305) 243 4037 Fax
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