Catheter associated urinary tract infections (CAUTIs): laboratory and clinical evaluation of a novel biofilm resistant polymer coating
Publication Date
March 15, 2022
Creator
Abstract
Biofilm formation on indwelling urinary catheters causes severe complications in catheterized patients and is commonly linked to symptomatic catheter associated urinary tract infections (CAUTI). The presence of urease producing bacteria, such as Proteus mirabilis and Pseudomonas aeruginosa, within the biofilm increases the urinary pH, resulting in the precipitation of minerals such as struvite and apatite. The resulting crystalline biofilm can encrust the catheter and result in blockage of urine flow. CAUTI prevention measures such as silver impregnation and antimicrobial catheter coatings, have exhibited limitations in terms of effectiveness and development of antimicrobial resistance.
Urinary catheters manufactured by Camstent Ltd., are coated with a novel polyacrylate copolymer of ethylene glycol dicyclopentenyl ether acrylate (EGDPEA) and di(ethyleneglycol) methyl ether methacrylate (DEGMA). The inability of bacteria to irreversibly attach to the weakly amphiphilic polymers such as EGDPEA inhibits biofilm formation. Combining EGDPEA with DEGMA confers the mechanical and lubricious properties desirable for a flexible coating compatible with implanted medical device applications.
The aim of this study was to demonstrate the ability of the EGDPEA/DEGMA coated Camstent catheters to resist biofilm formation, mineral accumulation, and fibrinogen deposition, and thus assess its potential to reduce symptomatic CAUTI episodes. The objectives were to quantify and compare the amount of biofilm and mineralization that accumulate on Camstent and silicone catheters in vitro in an intermittent flow bladder model and within a first-in-man clinical study. Preliminary biofilm and mineral quantification was via confocal fluorescence microscopy and image analysis, after staining with Syto64 and calcein, respectively. Environmental scanning electron microscopy (ESEM) coupled with energy dispersive X-ray spectroscopy (EDS) were carried out to characterize and compare the morphologies and chemistry of biofilm and minerals associated with Camstent and silicone catheters. 16S rRNA analysis was also carried out to determine any differences in the bacterial species colonizing they two types of surface.
Catheterization damages the mucosal lining of the patient’s bladder resulting in an immune response, where host proteins such as fibrinogen can cover the catheter surface and promote bacterial attachment. Consequently, the comparative impact of silicone and Camstent catheterization on urine fibrinogen content and catheter deposition was investigated using ELISA and immunohistochemistry.
Within an in vitro bladder model, Camstent catheters exhibited an improved resilience to P. mirabilis and Ps. aeruginosa biofilm formation in comparison with silicone catheters (Ps. aeruginosa- 2.55x104 µg cm-2 vs 4.46x104 µg cm-2 , P. mirabilis- 3.37x103 µg cm-2 vs 1.14x104 µg cm-2 , dualspecies inoculation- 3.75x104 µg cm-2 vs 6.31x104 µg cm-2 , respectively; P<0.05). Additionally, Camstent catheters did not become blocked during any of the experiments using the bladder model, whereas silicone devices were blocked after 57 hours on average following P. mirabilis infections, and after an average of 38 hours following dual-species infections with P. mirabilis and Ps. aeruginosa.
Bladder model experiments were also conducted using non-swarming and urease negative P. mirabilis transposon mutants. Urease production was shown to be detrimental to silicone catheter blockage, with ureR mutants found to be incapable of blocking silicone catheters within the in vitro bladder model. Bladder model inoculations with the non-swarming flgI mutant resulted in significantly higher biofilm biomass formed on silicone catheters when compared with the wild-type P. mirabilis strain. Bladder model experiments inoculating Camstent catheters with the flgI mutant however resulted in no blockage, and significantly less biofilm biomass, in comparison with silicone catheters inoculated with the mutant (1.83 x103 µg cm-2 vs. 5.10 x103 µg cm- 2 , respectively; P<0.05).
Urinary catheters were recovered from hospitalized patients were separated in to three clinical catheter cohorts predominantly defined by indwelling time (Average indwelling time: Cohort 1- 7 days, Cohort 2- 12 days, and Cohort 3- 23 days). A comparison of Camstent catheters (n=65) with silicone catheters (n=60), across the three clinical cohorts, revealed a significantly lower biofilm formation on the Camstent devices (Cohort 1- 0.037 µg cm-2 vs 4.425 µg cm-2 , Cohort 2- 0.003 µg cm-2 vs 0.022 µg cm-2 , Cohort 3- 8.634 µg cm-2 vs 20.039 µg cm2 , respectively; P<0.05). Further characterization of the biofilm and mineral associated with the two surfaces through ESEM imaging and EDS analysis revealed major differences in the morphology and chemistry of the minerals deposited on Camstent catheters compared with silicone devices. Struvite, apatite, and calcium carbonate were among the biofilm associated minerals found on silicone catheters, whereas a thin layer of calcium oxalate minerals, products of endogenous metabolism, was found on Camstent catheters. 16S rRNA analysis on the two types of surface also revealed marked differences in microbial community composition.
Quantification of fibrinogen within urine samples from hospitalized patients revealed that catheterization with Camstent catheters (n=3; 1.8 µg ml-1 ) results in a smaller increase in urinary fibrinogen compared with silicone (n=8; 3.5 µg ml-1 ). Analysis of the catheters associated with the urine samples also showed that Camstent catheter surfaces (n=3; 14.0 µg cm-2 ) accumulated less fibrinogen in comparison with silicone surfaces (n=4; 155.4 µg cm-2 ), despite comparable average post-catheterisation urinary fibrinogen concentrations (3.7 µg ml-1 vs. 5.3 µg ml-1 , respectively)
The in vitro and first-in-man data presented within this study provide evidence that the Camstent coated catheter effectively reduced biofilm formation and mineralization. Additionally, preliminary clinical data suggested that catheterization with Camstent catheters in lower urine fibrinogen and less fibrinogen deposition on the catheter than on silicone. This highlights the potential of the Camstent coating to reduce biofilm formation by Gram positive pathogens such as Enterococcus faecalis and Staphylococcus aureus that express fibrinogen receptors. Further clinical studies will be required to fully establish the potential of Camstent catheters to prevent CAUTIs.
Item Type
ethesis
Thesis Type
PhD
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Subjects (LC)
Associated Schools / Departments
School of Life Sciences
eprints ID
67106
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Kiril Kalenderski- Catheter associated urinary tract infections (CAUTIs)- laboratory and clinical evaluation of a novel-CorrectionsApplied-04-10-21.pdf
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