Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual's susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus-positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus. Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA-Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB − strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host's robust immune response.host-pathogen interactions | MRSA CAUTI | ClfB-fibrinogen interactions

# These authors contributed equally to this work. AbstractPurpose-Catheter-associated urinary tract infections (CAUTI) account for ~40% of all hospitalacquired infections worldwide, with more than one million cases diagnosed annually. Recent data from a CAUTI animal model has shown that inflammation induced by catheterization releases host fibrinogen that accumulates on the catheter. Further, Enterococcus faecalis catheter colonization was found to be dependent on EbpA, a fibrinogen binding adhesin. We sought to evaluate this mechanism in a human model. Materials and methods-Urinary catheters were collected from human subjects hospitalized for surgical or non-surgical urologic procedures. Catheters were subjected to immunofluorescence analyses by incubating them with anti-fibrinogen antibody and then stained for fluorescence. The fluorescence intensity was compared to standard catheters. Catheters were incubated with strains of Enterococcus faecalis, Staphylococcus aureus, or Candida to assess their binding to fibrinogenladen catheters.Results-Fifty catheters were collected after various surgical and urological procedures. In vivo dwell time ranged from 1 hour to 59 days. All catheters had fibrinogen deposition and its accumulation was dependent on dwell time but not on surgical procedure or catheter material. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of interest: No author has any conflicts of interest to disclose HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptCatheters were probed ex vivo with E. faecalis, S. aureus, and Candida albicans, which bound to catheters only in those regions where fibrinogen was deposited.Conclusions-Taken together, these data show that urinary catheters act as a binding surface for accumulation of fibrinogen, which is released due to inflammation resulting from a urological procedure or from catheter placement, creating a niche that can be exploited by uropathogens to cause CAUTI.

Gram-positive bacteria in the genus Enterococcus are a frequent cause of catheter-associated urinary tract infection (CAUTI), a disease whose treatment is increasingly challenged by multiantibiotic-resistant strains. We have recently shown that E. faecalis uses the Ebp pilus, a heteropolymeric surface fiber, to bind the host protein fibrinogen as a critical step in CAUTI pathogenesis. Fibrinogen is deposited on catheters due to catheter-induced inflammation and is recognized by the N-terminal domain of EbpA (EbpANTD), the Ebp pilus’s adhesin. In a murine model, vaccination with EbpANTD confers significant protection against CAUTI. Here, we explored the mechanism of protection using passive transfer of immune sera to show that antisera blocking EbpANTD-fibrinogen interactions not only is prophylactic but also can act therapeutically to reduce bacterial titers of an existing infection. Analysis of 55 clinical CAUTI, bloodstream, and gastrointestinal isolates, including E. faecalis, E. faecium, and vancomycin-resistant enterococci (VRE), revealed a diversity of levels of EbpA expression and fibrinogen-binding efficiency in vitro. Strikingly, analysis of 10 strains representative of fibrinogen-binding diversity demonstrated that, irrespective of EbpA levels, EbpANTD antibodies were universally protective. The results indicate that, despite diversity in levels of fibrinogen binding, strategies that target the disruption of EbpANTD-fibrinogen interactions have considerable promise for treatment of CAUTI.

Our prospective study demonstrated multiple factors that increase the relative risk of nephrolithiasis after Roux-en-Y gastric bypass. These changes may make stone formation after Roux-en-Y gastric bypass increasingly likely and pose an ongoing challenge in the realm of urology.

PurposeThe goal of this study was to compare the rate of systemic inflammatory response syndrome (SIRS) in high-risk patients undergoing percutaneous nephrolithotomy (PCNL) between patients who received 7, 2, or 0 days of preoperative antibiotics.Materials and MethodsWe retrospectively reviewed a series of consecutive PCNLs performed at our institution. Patients with infected preoperative urine cultures were excluded. High-risk patients were defined as those with a history of previous urinary tract infection (UTI), hydronephrosis, or stone size ≥2 cm. Patients were treated with 7, 2, or 0 days of preoperative antibiotic prophylaxis prior to PCNL. All patients received a single preoperative dose of antibiotics within 60 minutes of the start of surgery. Fisher exact test was used to compare the rate of SIRS by preoperative antibiotic length.ResultsOf the 292 patients identified, 138 (47.3%) had sterile urine and met high-risk criteria, of which 27 (19.6%), 39 (28.3%), and 72 (52.2%) received 7, 2, and 0 days of preoperative antibiotics, respectively. The 3 groups were similar in age, sex, and duration of surgery (p>0.05). There was no difference in the rate of SIRS between the groups, with 1 of 27 (3.7%), 2 of 39 (5.1%) and 3 of 72 patients (4.2%) meeting criteria in the 7, 2, and 0 days antibiotic groups (p=~1).ConclusionsExtended preoperative antibiotic prophylaxis was not found to reduce the risk of SIRS after PCNL in our institutional experience of high-risk patients. For these patients, a single preoperative dose of antibiotics is sufficient.