Urinary Catheter Encrustation Research Articles

Infection responsive coatings to reduce biofilm formation and encrustation of urinary catheters.

The care of patients undergoing long-term urethral catheterization is frequently complicated by Proteus mirabilis infection. This organism forms dense, crystalline biofilms, which block catheters leading to serious clinical conditions. However, there are currently no truly effective approaches to control this problem. Here, we describe the development of a novel theranostic catheter coating, to simultaneously provide early warning of blockage, and actively delay crystalline biofilm formation. The coating comprises of a pH sensitive upper polymer layer (poly(methyl methacrylate-co-methacrylic acid); Eudragit S 100®) and a hydrogel base layer of poly(vinyl alcohol), which is loaded with therapeutic agents (acetohydroxamic acid or ciprofloxacin hydrochloride) and a fluorescent dye, 5(6)-carboxyfluorescein (CF). The elevation of urinary pH due to P. mirabilis urease activity results in the dissolution of the upper layer and release of cargo agents contained in the base layer. Experiments using in vitro models, which were representative of P. mirabilis catheter-associated urinary tract infections, demonstrated that these coatings significantly delay time taken for catheters to block. Coatings containing both CF dye and ciprofloxacin HCl were able to provide an average of ca. 79h advanced warning of blockage and extend catheter lifespan ca. 3.40-fold. This study has demonstrated the potential for theranostic, infection-responsive coatings to form a promising approach to combat catheter encrustation and actively delay blockage.

New isolate from Salvinia molesta with antioxidant and urease inhibitory activity.

Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using solvents of increasing polarity. A series of column chromatography and later HPLC were performed on butanol extract. The structures of the resulting pure compounds were resolved using NMR (1D and 2D), infrared, and mass spectroscopy. The novel isolate was evaluated for antioxidant activity (using DPPH, superoxide anion radical scavenging, oxidative burst, and Fe+2 chelation assays), anti-glycation behavior, anticancer activity, carbonic anhydrase inhibition, phosphodiesterase inhibition, and urease inhibition. One new glucopyranose derivative 6'-O-(3,4-dihydroxybenzoyl)-4'-O-(4-hydroxybenzoyl)-α/β-D-glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC50 values of 48.2 ± 0.3, 60.3 ± 0.6, and 42.1 ± 1.8μM against DPPH, superoxide radical, and oxidative burst, respectively. Its IC50 in the Jack bean urease inhibition assay was 99.1 ± 0.8μM. The mechanism-based kinetic studies presented that compound 1 is a mixed-type inhibitor of urease with a Ki value of 91.8 ± 0.1μM. Finally, molecular dynamic simulations exploring the binding mode of compound 1 with urease provided quantitative agreement between estimated binding free energies and the experimental results. The studies corroborate the use of compound 1 as a lead for QSAR studies as an antioxidant and urease inhibitor. Moreover, it needs to be further evaluated through the animal model, that is, in vivo or tissue culture-based ex-vivo studies, to establish their therapeutic potential against oxidative stress phosphodiesterase-II and urease-induced pathologies.

A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections

Infection and blockage of indwelling urinary catheters is significant owing to its high incidence rate and severe medical consequences. Bacterial enzymes are employed as targets for small molecular intervention in human bacterial infections. Urease is a metalloenzyme known to play a crucial role in the pathogenesis and virulence of catheter-associated Proteus mirabilis infection. Targeting urease as a therapeutic candidate facilitates the disarming of bacterial virulence without affecting bacterial fitness, thereby limiting the selective pressure placed on the invading population and lowering the rate at which it will acquire resistance. We describe the design, synthesis, and in vitro evaluation of the small molecular enzyme inhibitor 2-mercaptoacetamide (2-MA), which can prevent encrustation and blockage of urinary catheters in a physiologically representative in vitro model of the catheterized urinary tract. 2-MA is a structural analogue of urea, showing promising competitive activity against urease. In silico docking experiments demonstrated 2-MA’s competitive inhibition, whilst further quantum level modelling suggests two possible binding mechanisms.

Molecular Docking of Natural Phenolic Compounds for the Screening of Urease Inhibitors.

Bacterial ureases have been the cause of various human and animal pathogenicity including hepatic encephalopathy, hepatic coma urolithiasis, gastric and peptic ulcers, pyelonephritis, and urinary catheter encrustation by the production of ammonia. Hence, in view of the side effects of existing drugs, there is a strong need to discover, more safe, effective and potent compounds for the treatment of infections caused by urease. For this purpose, several natural phenolic compounds have been screened by molecular modelling techniques, wherein the phenolic compounds were docked to the active site of Jack bean urease (PDB ID 3LA4) using the Schrodinger docking software. The lead compounds were identified via in-silico screening technique where docking score, binding energy, ADME and toxicity data were considered to screen the lead compounds as compared with the available standard drugs. From the docking study of screened natural phenolic compounds, five compounds diosmin, morin, chlorogenic acid, capsaicin and resveratrol were selected based upon their better affinity towards the receptor and were considered for further wet lab studies. The in-silico results were confirmed by in vitro experiments by use of the Jack bean urease using Weatherburn method.

An antimicrobial impregnated urinary catheter that reduces mineral encrustation and prevents colonisation by multi-drug resistant organisms for up to 12 weeks

Two major complications of indwelling urinary catheterisation include infection and mineral encrustation of the catheter. Our antimicrobial urinary catheter (AUC) impregnated with rifampicin, triclosan, and sparfloxacin has demonstrated long-term protective activity against major uropathogens. This study aimed to firstly assess the ability of the AUC to resist mineral encrustation in the presence and absence of bacteria. Secondly, it aimed to investigate the AUC’s anti-biofilm activity against multi-drug resistant organisms. There was no difference in surface roughness between AUC and control segments. In a static and a perfusion model, phosphate deposition was significantly reduced on AUCs challenged with P. mirabilis. Furthermore, none of the AUCs blocked during the 28 day test period, unlike controls. The AUC prevented colonisation by methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum beta-lactamase producing E. coli, and carbapenemase-producing E. coli for 12 consecutive weekly challenges. All three drugs impregnated into the catheter continued to exert protective activity throughout 12 weeks of constant perfusion. The drugs appear to migrate into the crystalline biofilm to continually protect against bacteria not it direct contact with the catheter surface. In conclusion, the AUC reduces mineral encrustation and may increase time to blockage in the presence of P. mirabilis, and does not predispose to mineral deposition under other conditions. It also offers 12 weeks of protection against multi-drug resistant bacteria. Statement of significanceInfection and associated mineral encrustation of urinary catheters are two serious complications of indwelling urinary catheters. Others have attempted to address this through various technologies such as coatings, dips, and surface modifications to prevent infection and/or encrustation. However, all current ‘anti-infective’ urinary catheter technologies are limited to short-term use. Some patients with spinal injuries, multiple sclerosis, stroke survivors and others use long-term catheters for 4–12 weeks at a time with multiple catheterisation possibly throughout the rest of their life. We present a urinary catheter for long-term use that is impregnated with three antimicrobials by a patient-protected process to prevent infection and encrustation for up to 12 weeks, the maximum lifetime of a long-term catheter before it is changed.

Prevention of encrustation and blockage of urinary catheters by Proteus mirabilis via pH-triggered release of bacteriophage.

The crystalline biofilms of Proteus mirabilis can seriously complicate the care of patients undergoing long-term indwelling urinary catheterisation. Expression of bacterial urease causes a significant increase in urinary pH, leading to the supersaturation and precipitation of struvite and apatite crystals. These crystals become lodged within the biofilm, resulting in the blockage of urine flow through the catheter. Here, we describe an infection-responsive surface coating for urinary catheters, which releases a therapeutic dose of bacteriophage in response to elevated urinary pH, in order to delay catheter blockage. The coating employs a dual-layered system comprising of a lower hydrogel 'reservoir' layer impregnated with bacteriophage, capped by a 'trigger' layer of the pH-responsive polymer poly(methyl methacrylate-co-methacrylic acid) (EUDRAGIT®S 100). Evaluation of prototype coatings using a clinically reflective in vitro bladder model system showed that catheter blockage time was doubled (13 h to 26 h (P < 0.05)) under conditions of established infection (108 CFU ml-1) in response to a 'burst-release' of bacteriophage (108 PFU ml-1). Coatings were stable both in the absence of infection, and in the presence of urease-negative bacteria. Quantitative and visual analysis of crystalline biofilm reduction show that bacteriophage constitute a promising strategy for the prevention of catheter blockage, a clinical problem for which there is currently no effective control method.

Bacteriophage Can Prevent Encrustation and Blockage of Urinary Catheters by Proteus mirabilis.

Proteus mirabilis forms dense crystalline biofilms on catheter surfaces that occlude urine flow, leading to serious clinical complications in long-term catheterized patients, but there are presently no truly effective approaches to control catheter blockage by this organism. This study evaluated the potential for bacteriophage therapy to control P. mirabilis infection and prevent catheter blockage. Representative in vitro models of the catheterized urinary tract, simulating a complete closed drainage system as used in clinical practice, were employed to evaluate the performance of phage therapy in preventing blockage. Models mimicking either an established infection or early colonization of the catheterized urinary tract were treated with a single dose of a 3-phage cocktail, and the impact on time taken for catheters to block, as well as levels of crystalline biofilm formation, was measured. In models of established infection, phage treatment significantly increased time taken for catheters to block (∼ 3-fold) compared to untreated controls. However, in models simulating early-stage infection, phage treatment eradicated P. mirabilis and prevented blockage entirely. Analysis of catheters from models of established infection 10 h after phage application demonstrated that phage significantly reduced crystalline biofilm formation but did not significantly reduce the level of planktonic cells in the residual bladder urine. Taken together, these results show that bacteriophage constitute a promising strategy for the prevention of catheter blockage but that methods to deliver phage in sufficient numbers and within a key therapeutic window (early infection) will also be important to the successful application of phage to this problem.

Irrigation with N,N-dichloro-2,2-dimethyltaurine (NVC-422) in a citrate buffer maintains urinary catheter patency in vitro and prevents encrustation by Proteus mirabilis.

Long-term use of indwelling urinary catheters can lead to urinary tract infections and loss of catheter patency due to encrustation and blockage. Encrustation of urinary catheters is due to formation of crystalline biofilms by urease-producing microorganisms such as Proteus mirabilis. An in vitro catheter biofilm model (CBM) was used to evaluate current methods for maintaining urinary catheter patency. We compared antimicrobial-coated urinary Foley catheters, with both available catheter irrigation solutions and investigational solutions containing NVC-422 (N,N-dichloro-2,2-dimethyltaurine; a novel broad-spectrum antimicrobial). Inoculation of the CBM reactor with 10(8) colony-forming units of P. mirabilis resulted in crystalline biofilm formation in catheters by 48h and blockage of catheters within 5days. Silver hydrogel or nitrofurazone-coated catheters did not extend the duration of catheter patency. Catheters irrigated daily with commercially available solutions such as 0.25% acetic acid and isotonic saline blocked at the same rate as untreated catheters. Daily irrigations of catheters with 0.2% NVC-422 in 10mM acetate-buffered saline pH 4 or Renacidin maintained catheter patency throughout 10-day studies, but P. mirabilis colonization of the CBM remained. In contrast, 0.2% NVC-422 in citrate buffer (6.6% citric acid at pH 3.8) resulted in an irrigation solution that not only maintained catheter patency for 10days but also completely eradicated the P. mirabilis biofilm within one treatment day. These data suggest that an irrigation solution containing the rapidly bactericidal antimicrobial NVC-422 in combination with citric acid to permeabilize crystalline biofilm may significantly enhance catheter patency versus other approved irrigation solutions and antimicrobial-coated catheters.

Encrustations of the urinary catheter and prevention strategies: a literature review

Patients with an indwelling urinary catheter are at risk of developing urinary tract infection: for each day of the catheter remaining in situ, there is an increasing risk from 3% to 7% for infection to appear. One of the main complications of catheterization is the onset of encrustations, frequently resulting in obstruction of the catheter. Aim of this study is to describe the problem of indwelling urinary catheter encrustation and prevention strategies. A narrative review of the literature was conducted. Indwelling urinary catheter encrustations originate more easily when urine contains high concentrations of poorly soluble constituents and when the state of the urinary tract enables their precipitation as an alkaline urinary pH, often associated with the presence of bacteria urease-producers, for instance Proteus mirabilis. Urease can generate crystals and this process keeps going until the accumulation of crystalline deposits block the urine flow within the catheter lumen. The literature suggests that there are manifold pharmacological and non-pharmacological strategies to prevent encrustations. The literature analysis suggests that the permanence of the catheter could potentially be one of the most relevant causes of encrustation. The catheterization duration is the most important risk factor for bacteriuria, essential for the process of encrustation to start off. There are many prevention strategies, among which promotion of nucleation pH (pHn) supplementation in the daily diet with liquids containing citrate; this is the most simple and suitable for all patients being inexpensive and effective.

Development of an antimicrobial urinary catheter to inhibit urinary catheter encrustation

Background: Encrustation of urinary catheters is a frequent problem in patients with long-term indwelling catheters colonised with urease-positive bacteria such as Proteus mirabilis. Catheter blockage may follow catheter encrustation, potentially leading to systemic infection. Prevention of encrustation is difficult and avoidance of recurrence often unsuccessful. One possible preventative strategy is to use a catheter with an antimicrobial surface and development and assessment of such a surface was the aim of this research. Methods: Initial experiments assessed the antimicrobial activity of silicone impregnated with plant-derived antimicrobials and triclosan using agar diffusion. The longevity of activity of each antimicrobial silicone was examined over a period of 11 weeks following soaking individual pieces of antimicrobial silicone in an artificial urine solution before using agar diffusion to test remaining antimicrobial activity. Live/Dead staining of bacteria colonising the surface of each antimicrobial silicone was employed to determine the bactericidal properties of each antimicrobial silicone. Selected antimicrobial silicones were subsequently evaluated for their ability to prevent catheter encrustation in an in vitro bladder model. Results: Results showed that antimicrobial activity was obtained using 1% triclosan-impregnated silicone and that this antimicrobial activity was long-lasting (up to 11 weeks). Use of a dip coat silicone formulation, containing 0.2% triclosan, proved effective at delaying catheter encrustation with P. mirabilis metabolites in vitro. In 8 out of 13 independent experiments using dip-coated catheters, no catheter blockage occurred over 7 days, whilst all control catheters blocked during this period. Only on one occasion was delayed encrustation not evident with the treated catheters. Conclusions: In summary, a dip-coat silicone containing triclosan proved effective in preventing in vitro catheter encrustation caused by P. mirabilis infection. Further studies with triclosan silicone dip coat formulation are warranted, including those that investigate potential host cell toxicity and long-term benefits following its application to indwelling urinary catheters in clinical settings.

A new urease inhibitor from Viola betonicifolia.

Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.

A High Throughput, Minimally Invasive, Ultrasound Guided Model for the Study of Catheter Associated Urinary Tract Infections and Device Encrustation in Mice

Catheter associated urinary tract infections are one of the most common health care associated infections. The condition is frequently complicated by encrustation, which blocks the catheter lumen. Preclinical research is limited by the lack of relevant high throughput and cost-effective animal models. Current models are restricted to female mice, associated with major transurethral loss of catheter materials during micturition, highly invasive and complex. We present an ultrasound guided, minimally invasive model that enables catheter associated urinary tract infection and catheter encrustation studies in each mouse gender. Catheter segments (4 mm) were implanted in murine bladders percutaneously in 15 males and 5 females, and transurethrally in 15 females using the Seldinger technique under ultrasound guidance. Proteus mirabilis was instilled intraluminally. Catheter encrustation was monitored by ultrasound. Bacteria were quantified in urine, and catheters and encrustation were analyzed on day 6 or 21. Percutaneous and transurethral catheter implantations were performed in a mean ± SE 3.6 ± 0.8 vs 2.5 ± 0.5 minutes in all mice. Ultrasound confirmed that 100% and 66% of implanted catheters, respectively, remained indwelling during the study period. Catheter encrustation developed in P. mirabilis infected urine 48 hours after instillation and an increase with time was detected by ultrasound. Fourier transform spectroscopy of the encrustation confirmed a typical struvite spectrum. Control catheters remained sterile during 21 days. Our minimally invasive, reproducible percutaneous technique is suitable for studying catheter associated urinary tract infection in each gender. Infecting urine with P. mirabilis generates a preclinical model of catheter encrustation within 3 days. The progression of encrustation can be monitored invivo by ultrasound, making this image based model suitable for assessing novel antibacterial and anti-encrustation therapies.

A clinical evaluation of a sensor to detect blockage due to crystalline biofilm formation on indwelling urinary catheters

To test the performance and acceptability of an early warning sensor to predict encrustation and blockage of long-term indwelling urinary catheters. In all, 17 long-term indwelling catheter users, 15 'blockers' and two 'non-blockers' (controls) were recruited; 11 participants were followed prospectively until catheter change, three withdrew early and three did not start. Two sensors were placed in series between the catheter and the urine bag at catheter change. The sensor nearest the bag was changed at the same time as the bag change (weekly); the sensor nearest the catheter remained in situ for the duration of the catheter's life. Bacteriology and pH determinations were performed on urine samples at each bag, sensor and catheter change. The colour of the sensors was recorded daily. On removal, each sensor and the catheter were examined for visible evidence of encrustation and blockage. Participants were asked to keep a daily diary to record colour change and any other relevant observations and to complete a psychosocial impact of assistive devices tool at the end of the study. Participants and carers/healthcare professionals (when involved in urine bag or catheter change) were asked to complete a questionnaire about the sensor. Urease-producing bacteria were isolated from seven of the 14 patients (including early withdrawals; P. mirabilis in four, Morganella or Providencia in three). In six of the seven patients the sensors turned blue-black; two of these were early withdrawals, two went to planned catheter change (one of these was recruited as a 'non-blocker') and three had catheter blockage. The number of days of catheterisation before blockage was 22, 23 and 25 days, and the sensor changed colour within 24-48 h after insertion. The urine mean (range) pH of the sensors that turned blue-black was 7.6 (5.5-9.0) and of the sensors that remained yellow 6.1 (5.1-7.5). The sensor was generally well-received and was positive in the psychosocial assessment. The sensor is a useful indicator of urine pH and of the conditions that lead to catheter blockage. It may be particularly useful for new indwelling catheter users. To be a universally acceptable predictor of catheter blockage, the time from sensor colour change to blockage needs to be reduced.

Pulling out of the Urinary Catheter together with Double-J Stent which is Penetrated to the Tip of the Foley after a Renal Transplantation: A Case Report

Today kidney transplantation is the best treatment choice of end stage renal failure. Double-j catheters have been used in renal transplant patients to prevent urinary leakage and ureteric obstruction but these catheters have many complications like urinary tract infection, obstruction, catheter encrustation, perforation and migration. Although these complications, double-j catheters are now widely used in urological practice. Yet there is controversy among transplant surgeons in the routine use of these

Development of an “early warning” sensor for encrustation of urinary catheters following Proteus infection

Biofilm formation in long-term urinary catheterized patients can lead to encrustation and blockage of urinary catheters with serious clinical complication. Catheter encrustation stems from infection with urease-producing bacteria, particularly Proteus mirabilis. Urease generates ammonia from urea, and the elevated pH of the urine results in crystallization of calcium and magnesium phosphates, which block the flow of urine. The aim of this research is to develop an "early warning" silicone sensor for catheter encrustation following bacterial infection of an in vitro bladder model system. The in vitro bladder model was infected with a range of urease positive and negative bacterial strains. Developed sensors enabled catheter blockage to be predicted ~17-24 h in advance of its occurrence. Signaling only occurred following infection with urease positive bacteria and only when catheter blockage followed. In summary, sensors were developed that could predict urinary catheter blockage in in vitro infection models. Translation of these sensors to a clinical environment will allow the timely and appropriate management of catheter blockage in long-term catheterized patients.

Use of quorum sensing antagonists to deter the formation of crystalline Proteus mirabilis biofilms

Proteus mirabilis biofilms are a major cause of urinary catheter blockage. Antibiotic-impregnated catheters used to prevent catheter blockage have achieved limited success. Research has examined the efficacy of quorum sensing inhibitors against Pseudomonas aeruginosa biofilms, but there are few reports of the effects of these compounds against crystalline P. mirabilis biofilms. This study examined the effect of two quorum sensing antagonists, p-nitrophenyl glycerol (PNPG) and tannic acid, against crystalline P. mirabilis biofilms. Tannic acid and PNPG were observed to inhibit the quorum sensing system and the formation of P. mirabilis biofilms grown in artificial urine. The success of these compounds provides a possible means of preventing urinary catheter encrustation.

A Sensor To Detect the Early Stages in the Development of CrystallineProteus mirabilisBiofilm on Indwelling Bladder Catheters

A simple sensor has been developed to detect the early stages of urinary catheter encrustation and avoid the clinical crises induced by catheter blockage. In laboratory models of colonization by Proteus mirabilis, the sensor signaled encrustation at an average time of 43 h before catheters were blocked with crystalline biofilm.

PH testing in catheter maintenance: the clinical debate.

The pH of urine is widely recognized as being a major contributory factor in urinary catheter encrustation. What is less widely appreciated is the range of factors that affect the pH of urine, and which therefore affect the reliability and validity of urine pH testing. This article examines the validity of various urinary pH testing methods and discusses the theoretical and practical implications of the uncertainty surrounding their practical value.

Managing recurrent urinary catheter encrustation.

Recurrent blockage of the urinary catheter is a common problem in around 40-50% of long-term catheterized patients, leading to problems which are distressing to patients and costly to health services in both time and resources. Blockage is frequently caused by the build-up of mineral deposits on the catheter surface following precipitation from the urine under alkaline conditions. The presence of urea-splitting bacteria in the urine promotes a strongly alkaline urine and their adhesion to the catheter as a biofilm makes them extremely difficult to remove. This article addresses strategies for early identification of potential 'blockers'; proactive approaches to care; and the evidence for use of catheter maintenance solutions.

Catheter associated urinary tract infection and encrustation

This paper examines the relationship between urinary pH, infection and urinary catheter encrustation and discusses the current management and problems of catheter associated urinary infection and encrustation.