SUMMARY Catheter-associated urinary tract infections (CAUTIs) represent the most common type of nosocomial infection and are a major health concern due to the complications and frequent recurrence. These infections are often caused by Escherichia coli and Proteus mirabilis. Gram-negative bacterial species that cause CAUTIs express a number of virulence factors associated with adhesion, motility, biofilm formation, immunoavoidance, and nutrient acquisition as well as factors that cause damage to the host. These infections can be reduced by limiting catheter usage and ensuring that health care professionals correctly use closed-system Foley catheters. A number of novel approaches such as condom and suprapubic catheters, intermittent catheterization, new surfaces, catheters with antimicrobial agents, and probiotics have thus far met with limited success. While the diagnosis of symptomatic versus asymptomatic CAUTIs may be a contentious issue, it is generally agreed that once a catheterized patient is believed to have a symptomatic urinary tract infection, the catheter is removed if possible due to the high rate of relapse. Research focusing on the pathogenesis of CAUTIs will lead to a better understanding of the disease process and will subsequently lead to the development of new diagnosis, prevention, and treatment options.

Bacteria have a basic survival strategy: to colonize surfaces and grow as biofilm communities embedded in a gel-like polysaccharide matrix. The catheterized urinary tract provides ideal conditions for the development of enormous biofilm populations. Many bacterial species colonize indwelling catheters as biofilms, inducing complications in patients' care. The most troublesome complications are the crystalline biofilms that can occlude the catheter lumen and trigger episodes of pyelonephritis and septicemia. The crystalline biofilms result from infection by urease-producing bacteria, particularly Proteus mirabilis. Urease raises the urinary pH and drives the formation of calcium phosphate and magnesium phosphate crystals in the biofilm. All types of catheter are vulnerable to encrustation by these biofilms, and clinical prevention strategies are clearly needed, as bacteria growing in the biofilm mode are resistant to antibiotics. Evidence indicates that treatment of symptomatic, catheter-associated urinary tract infection is more effective if biofilm-laden catheters are changed before antibiotic treatment is initiated. Infection with P. mirabilis exposes the many faults of currently available catheters, and plenty of scope exists for improvement in both their design and production; manufacturers should take up the challenge to improve patient outcomes.

Abstract. Stickler DJ (Cardiff University, Cardiff, UK). Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done. (Review). J Intern Med 2014; 276: 120-129.This review is largely based on a previous paper published in the journal Spinal Cord. The care of many patients undergoing long-term bladder catheterization is complicated by encrustation and blockage of their Foley catheters. This problem stems from infection by urease-producing bacteria, particularly Proteus mirabilis. These organisms colonize the catheter forming an extensive biofilm; they also generate ammonia from urea, thus elevating the pH of urine. As the pH rises, crystals of calcium and magnesium phosphates precipitate in the urine and in the catheter biofilm. The continued development of this crystalline biofilm blocks the flow of urine through the catheter. Urine then either leaks along the outside of the catheter and the patient becomes incontinent or is retained causing painful distension of the bladder and reflux of urine to the kidneys. The process of crystal deposition can also initiate stone formation. Most patients suffering from recurrent catheter encrustation develop bladder stones. P. mirabilis establishes stable residence in these stones and is extremely difficult to eliminate from the catheterized urinary tract by antibiotic therapy. If blocked catheters are not identified and changed, serious symptomatic episodes of pyelonephritis, septicaemia and endotoxic shock can result. All types of Foley catheters including silver-or nitrofurazonecoated devices are vulnerable to this problem. In this review, the ways in which biofilm formation on Foley catheters is initiated by P. mirabilis will be described. The implications of understanding these mechanisms for the development of an encrustation-resistant catheter will be discussed. Finally, the way forward for the prevention and control of this problem will be considered.

Proteus mirabilis is a common cause of catheter-associated urinary tract infection (C-UTI). It blocks indwelling urethral catheters through the formation of extensive crystalline biofilms. The obstruction of urine flow can induce episodes of pyelonephritis, septicemia, and shock. P. mirabilis exhibits a type of motility referred to as swarming, in which multicellular rafts of elongated, hyperflagellated swarmer cells form and move rapidly in concert over solid surfaces. It has been suggested that swarming is important in the pathogenesis of C-UTI. In this study we generated a set of stable transposon mutants deficient in swarming and used them to assess the role of swarming in the migration of P. mirabilis over urinary catheters. Swarming was found to be essential for migration over all-silicone catheters. Swarming-deficient mutants were attenuated in migration over hydrogel-coated latex catheters, but those capable of swimming motility were able to move over and infect these surfaces. A novel vapor fixation technique for the preparation of specimens and scanning electron microscopy were used to resolve the ultrastructure of P. mirabilis multicellular rafts. The flagellar filaments of P. mirabilis were found to be highly organized during raft migration and were interwoven in phase to form helical connections between adjacent swarmer cells. Mutants lacking these novel organized structures failed to swarm successfully. We suggest that these structures are important for migration and formation of multicellular rafts. In addition, the highly organized structure of multicellular rafts enables P. mirabilis to initiate C-UTI by migration over catheter surfaces from the urethral meatus into the bladder.Indwelling bladder catheterization is a convenient way to manage the problems of urinary retention and incontinence that afflict so many elderly and disabled people. The catheter, however, forms a bridge along which bacteria can pass from a contaminated external environment into a vulnerable body cavity. Even with meticulous nursing care, all patients undergoing catheterization for longer than a month will develop urinary tract infections (16). The number of catheterized patients is so large that catheter-associated urinary tract infections (C-UTI) are the most common infections acquired in hospitals and other health care facilities (29).Proteus mirabilis poses particular problems in the care of patients undergoing long-term indwelling bladder catheterization. Infections with this organism result in the formation of extensive crystalline biofilms on the catheters that can block the flow of urine from the bladder (28). The crystalline material, composed of magnesium and calcium phosphates, precipitates out of solution under the alkaline conditions generated by the P. mirabilis urease enzyme (5,13,20). The obstruction of the flow of urine through the catheter can induce serious complications. Urine either leaks around the outside of the catheter causing patients to become incontinent or is retained in the bladder resulting ...

Previous experimental investigations of the crystalline biofilms that colonize and block urinary catheters have focussed on their formation by pure cultures of Proteus mirabilis. In the urine of patients undergoing long-term catheterization, P. mirabilis is commonly found in mixed communities with other urinary tract pathogens. Little is known about the effect that the other species have on the rate at which P. mirabilis encrusts catheters. In the present study, a set of data on the nature of the bacterial communities on 106 catheter biofilms has been analysed and it was found that while species such as Providencia stuartii and Klebsiella pneumoniae were commonly associated with P. mirabilis, when Escherichia coli, Morganella morganii or Enterobacter cloacae were present, P. mirabilis was rarely or never found. The hypothesis that the absence of P. mirabilis from some biofilm communities could be due to its active exclusion by other species has also been examined. Experiments in laboratory models showed that co-infection of P. mirabilis with M. morganii, K. pneumoniae or E. coli had no effect on the ability of P. mirabilis to encrust and block catheters. Co-infection with Ent. cloacae or Pseudomonas aeruginosa, however, significantly increased the time that catheters took to block (P ,0.05). The growth of Ent. cloacae, M. morganii, K. pneumoniae or E. coli in the model for 72 h prior to superinfection with P. mirabilis significantly delayed catheter blockage. In the case of Ent. cloacae, for example, the mean time to blockage was extended from 28.7 h to 60.7 h (P ¡0.01). In all cases, however, P. mirabilis was able to generate alkaline urine, colonize the biofilms, induce crystal formation and block the catheters. The results suggest that although there is a degree of antagonism between P. mirabilis and some of the other urinary tract organisms, the effects are temporary and whatever the pre-existing urinary microbiota, infection with P. mirabilis is thus likely to lead to catheter encrustation and blockage.

The biofilm mode of growth has been implicated in the majority of human bacterial infections. In the urinary tract, notable biofilm-associated infections include prostatitis, chronic cystitis, struvite urolithiasis, and catheter-associated infections. Biofilms protect the causative organisms from host defences and antimicrobial therapy. Biofilm formation has traditionally been considered to result from adhesion and capsule formation by adherent microorganisms. Recent work has shown that a large number of genes are activated during this process, some of which have been associated with twitching motility, quorum sensing, and slow growth. In this paper, we review some of the recent work on biofilm biology and highlight its role in urinary tract infections, particularly those associated with urinary catheters.

Objectives: To review the literature showing that understanding how Foley catheters become encrusted and blocked by crystalline bacterial biofilms has led to strategies for the control of this complication in the care of patients undergoing long-term indwelling bladder catheterization. Methods: A comprehensive PubMed search of the literature published between 1980 and December 2009 was made for relevant articles using the Medical Subject Heading terms 'biofilms', 'urinary catheterization', 'catheter-associated urinary tract infection' and 'urolithiasis'. Papers on catheterassociated urinary tract infections and bacterial biofilms collected during 40 years of working in the field were also reviewed. Results: There is strong experimental and epidemiological evidence that infection by Proteus mirabilis is the main cause of the crystalline biofilms that encrust and block Foley catheters. The ability of P. mirabilis to generate alkaline urine and to colonize all available types of indwelling catheters allows it to take up stable residence in the catheterized tract in bladder stones and cause recurrent catheter blockage. Conclusion: The elimination of P. mirabilis by antibiotic therapy as soon as it appears in the catheterized urinary tract could improve the quality of life for many patients and reduce the current expenditure of resources when managing the complications of catheter encrustation and blockage. For patients who are already chronic blockers and stone formers, antibiotic treatment is unlikely to be effective owing to the resistance of cells in the crystalline biofilms. Strategies such as increasing fluid intake with citrated drinks could control the problem until bladder stone removal can be organized.

The problem of catheter encrustation stems from infection by urease-producing bacteria. These organisms generate ammonia from urea, elevate the pH of urine and cause crystals of calcium and magnesium phosphates to form in the urine and the biofilm that develops on the catheter. In this study, a laboratory model was used to compare the ability of 12 urease-positive species of urinary tract pathogens to encrust and block catheters. Proteus mirabilis, Proteus vulgaris and Providencia rettgeri were able to raise the urinary pH above 8.3 and produce catheter-blocking crystalline biofilms within 40 h. Morganella morganii and Staphylococcus aureus elevated the pH of urine to 7.4 and 6.9, respectively, and caused some crystal deposition in the biofilms but did not block catheters in the 96 h experimental period. Isolates of Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa and Providencia stuartii were only capable of raising the pH of urine to a maximum of 6.4 and failed to cause crystal deposition in the biofilm. The most effective way to prevent catheter encrustation was shown to be diluting urine and increasing its citrate concentration. This strategy raises the nucleation pH (pH n ) at which calcium and magnesium phosphates crystallize from urine. Increasing the fluid intake of a healthy volunteer with citrated drinks resulted in urine with a pH n of .8.0 in which catheter encrustation was inhibited. It is suggested that this dietary strategy will be an effective means of controlling catheter encrustation, whichever bacterial species is causing the problem.