Open access peer-reviewed chapter

# Role of Bacterial Biofilms in Catheter-Associated Urinary Tract Infections (CAUTI) and Strategies for Their Control

By Mary Anne Roshni Amalaradjou and Kumar Venkitanarayanan

Submitted: April 25th 2012Reviewed: April 16th 2013Published: July 10th 2013

DOI: 10.5772/55200

## 1. Introduction

Urinary tract infections (UTI’s) can be defined as bacteriuria (>105 CFU/mL in adults; >104 CFU/mL in children) of an uropathogen with associated clinical signs that include dysuria and urgency [18]. According to the United States Centers for Disease Control and Prevention (CDC), a symptomatic urinary tract infection must meet at least one of the following criteria:

• Patients had/did not have an indwelling catheter in place at the time of specimen collection or onset of signs or symptoms

• Patient has at least one of the following signs or symptoms with no other recognized cause: fever (>38oC), urgency, frequency, dysuria, suprapubic tenderness or costovetebral angle pain or tenderness

• Patient has a positive urine culture of ≥105 with no more than 2 species of microorganisms [20].

### 5.1. Need for and duration of catheterization

It is estimated that about 21-50% of catheters are placed without justified need and catheters are inappropriately retained for 33-50% of total device days [73, 101]. The most effective ways for the preventing CAUTI are by reducing the duration of catheterization and its early removal [51]. Use of interventions such as nurse prompted removal suggestions and computer based reminders to the patients have resulted in a decline in catheter retention and a concomitant reduction in bacteriuria [164]. Thus, it is important to refrain from using an indwelling catheter without an appropriate indication. A study conducted in an emergency department indicated that use of pre-insertion checklists have led to an improved adherence to indications for placement resulting in the increase in the number of appropriately placed catheters from 37% to 51% [50].

### 5.2. Catheter placement and management

Since the catheter provides a connection between the highly colonized perineum and the sterile bladder, sterility during catheter handling and placement is of greatest importance. In this regard, hand hygiene plays a vital role in the prevention of CAUTI [16]. Insertion of a catheter in the emergency room rather than an operating room has been shown to be associated with higher rates of catheter associated bacteriuria (CAB; 158). Use of an aseptic insertion technique reduces the risk of acquiring resistant organisms in the hospital [63]. A randomized study conducted by Platt and others [1983; 118] demonstrated that hospitalized patients intubated with a catheter without a pre-sealed junction were 2.7 times more likely to develop CAB than patients with pre-connected catheter drainage bags and sealed junctions. Therefore, the use of closed catheter drainage systems universally is recommended [63]. Similarly, any breach in the closed drainage system would also increase the risk for CAB. Any manipulation of the indwelling catheter should be avoided so that breaches in the closed drainage and shear trauma can be minimized [25].

### 5.3. Catheter design

Catheter design has not changed significantly since the inception of the Foley catheter in the 1930s [97]. In addition to the catheter design, biocompatibility of the material is crucial. Catheter material can also impact the rate of biofilm formation. Scanning electron microscopy imaging of latex catheters revealed that presence of more uneven surfaces on it than other silicone counterparts which can promote bacterial adhesion [150]. Additionally latex has been associated with toxic effects in vitro and proinflammatory reactions in vivo leading to polypoid cystitis on chronic exposure [49]. Moreover, silicone catheters are more popular to avoid allergic reactions associated with latex use. Besides being hypoallergenic, silicone catheters have a larger lumen and are minimally prone to encrustation by crystalline biofilms [36]. A newly engineered silicone catheter with a trefoil cross-section was shown to reduce CAB and inflammation when compared to a standard urinary catheter [153]. The trefoil conformation helps to minimize the surface area of contact between the catheter and the urethra, thereby decreasing friction and trauma and increasing drainage of urethral secretions [137].

### 5.4. Hydrogel coated catheters

Cross linked insoluble polymers that are hydrophilic and trap water are known as hydrogels. Use of hydrophilic coating on catheters has been shown to improve patient comfort, reduce bacterial adherence and encrustation. The presence of hydrogels also increases lubrication and decreases bacterial adhesion to the interface of the tissue and the catheter [11]. However, conflicting data exist on the ability of hydrogel coated catheters to reduce CAUTI, which could be attributed to the type of hydrogel incorporated. Tunney and Gorman [2002; 169] used in vitro models to demonstrate that Poly(vinyl pyrollidone)-coated polyurethane catheters had a lower rate of encrustation when compared to uncoated polyurethane and silicone catheters. Another study showed that the use of poly(ethylene oxide)-based multiblock copolymer and segmented polyurethane increased the time to encrustation and catheter blockage from 7.8 h to 20.1 h [116]. These findings collectively suggest that the type of hydrogel coating can affect the rate of encrustation and the resulting catheter blockage.

### 5.5. Antimicrobial coating

Antimicrobial modification of catheters is achieved by coating, matrix loading and immersion in an antimicrobial solution. The primary objective behind the incorporation of antimicrobial on a catheter is to reduce bacterial attachment and biofilm formation. Additionally, release of antimicrobials from the catheters into the milieu is also another potential approach to control planktonic cells of uropathogens [56].

#### 5.5.1. Nanoparticles and iontophoresis

Nanoparticles by virtue of their small size have the ability to penetrate bacterial cells, disrupt cell membranes and bind to the chromosomal DNA. Lelouche and others [2009; 84] demonstrated that glass surfaces coated with magnesium fluoride nanoparticles inhibited biofilm formation by S. aureus and E. coli, whereas magnesium fluoride solutions did not affect biofilm formation. This highlights the size dependent effect of nanoparticles.

The application of low intensity direct current (Ionotophoresis) in vitro has been shown to increase the antimicrobial activity of antibiotics on bacteria embedded in biofilms [27]. Chakravarti and others [2005; 21] used a urinary flow model to test the in vitro antibiofilm efficacy of iontophoretic silver wire containing silicone catheters. These catheters were challenged with P. mirabilis and then exposed to a steady current of 150 µA. It was observed that application of the electric field increased the time to blockage from 22 h to 156 h, and reduced the viable count from 109 CFU/ml to 104 CFU/ml. Similar in vivo study in sheep intubated with catheters containing platinum electrodes showed a decline in pathogen count from 107 CFU/ml to 103 CFU/ml on application of a direct current of 400 µA [33].

#### 5.5.2. Antimicrobials

A variety of antimicrobials applied on urinary catheters have been investigated for their efficacy in controlling UTIs using in vitro and in vivo models.Nitrous oxide is known to exhibit bactericidal activity [123]. Urinary catheters impregnated with gaseous nitrous oxide, a known antimicrobial, and challenged with E. coli resulted in the slow release of nitrous oxide into the urine for over 14 days, and decreased biofilm formation by E. coli. Chlorhexidine is a common antimicrobial used against oral plaques. In vivo studies in rabbits intubated with genidine (combination of chlorhexidine and gentian violet) coated silicone catheters showed a reduction in biofilm formation by E. coli, E. faecium, P. aeruginosa, K. pneumoniae and Candida in comparison to silver coated and uncoated catheters [54]. Catheter associated bacteriuria was noticed in 60% and 71% of the rabbits with uncoated catheters and silver hydrogel coated catheters, respectively, whereas CAB did not occur in any of the rabbits with genidine coated catheters. Similar to chlorhexidine, triclosan is another antibacterial ingredient in toothpastes and cleaners used in health care settings. Triclosan exerts its antibacterial effect by inhibiting bacterial fatty acid synthesis [147]. Incorporation of triclosan in the balloon of catheters resulted in its release and diffusion through latex and silicon catheter balloons. The balloon served as a reservoir and the membrane helped in controlled release of triclosan. This in turn slowed encrustation and maintained the lumen patent for 7 days as compared to 24 h in saline-filled catheters [150]. Another antibacterial shown to possess antibiofilm effect is nitrofurazone, which interferes with bacterial ribosomes, DNA and cell wall. When nitrofurazone coated catheters were compared with standard catheters, it was observed that nitrofurazone significantly reduced CAB [133]. Besides nitrofurazone, norfloxacin coated catheters were also shown to inhibit the growth of E. coli, K. pneumoniae and P. vulgaris for up to 10 days [115]. Similarly, gentamicin coated catheters were also effective in reducing CAB in rabbits [23]. Another study demonstrated that sparfloxacin coated and heparin coated catheters reduced colonization by S. aureus, E. coli and S. epidermidis for greater than 26 days compared to control catheters [79]. However, the use of antibiotics on catheters to control bacterial biofilms could potentially lead to the emergence of antibiotic resistant bacteria [126]. Repeated use of antibiotics for treating UTIs has been linked to the emergence of antibiotic resistant UPEC [41, 126]. Therefore, there is an increasing interest in the use of natural antimicrobials for controlling microbial infections, including UTIs.

#### 5.5.3. Plant molecules

Plants are capable of synthesizing a large number of molecules [47], most of which are produced as a defense mechanism against predation by microorganisms and insects. A variety of plant-derived polyphenols are active components in traditional medicines [178]. A significant body of literature exists on the positive effects of dietary intake of berry fruits on human health, performance and disease [134]. Cranberry products such as its juice and tablets have been used as an alternative medicine to prevent UTIs in humans for decades. Clinical and epidemiological studies support the use of cranberry in maintaining a healthy urinary tract [117]. Although several studies have tested the antimicrobial effect of cranberries against multiple uropathogens, it was found to be most effective against UPEC.

Cranberries exert anti-adhesive effects on certain uropathogens [112] and this effect is specific to certain components of cranberry [110]. Cranberries contain three different flavonoids (flavonols, anthocyanins and PAC), catechins, hydroxycinnamic and other phenolic acids and triterpenoids. The anthocyanins are absorbed in the human circulatory system and transported without any chemical change to the urine [117]. Cranberry products do not inhibit bacterial growth, but reduced bacterial adherence to uroepithelial cells, thereby decreasing the development of UTI. The anti-adhesive effects of p-fimbriated UPEC to uroepithelial cells are related with A-linked PAC as compared with lack of anti-adhesion activities of B-linked PAC from grape, apple juice, green tea and chocolate [67]. The A-type PAC in cranberries enhances the anti-adhesive effects in vitro and in urine. PAC binds to lipopolysaccharide in gram-negative bacteria. When E. coli was grown in the presence of cranberry components, the bacterial morphology changed to a more spherical cell-like form. These changes cause them to be repelled by the human cells [88]. Similar study by Tao and others [2011; 159] have also demonstrated that consumption of cranberry juice cocktail reduced the adhesion of UPEC to a silicon nitride probe.

Cranberry has undergone extensive evaluation in the management of UTIs. However, currently there is no evidence that cranberry can be used to treat UTIs. Hence, the focus has been on its use as a prophylactic agent in the prevention of UTIs [52]. The consumption of cranberry juice can help to prevent the adhesion of UPEC to the uroepithelium and thereby help reduce the incidence of UTIs. With rising concerns of antibiotic resistance among UPEC, cranberry could serve as an effective alternative in controlling UTIs.

Trans-cinnamaldehyde (TC) is a major component of the bark extract of cinnamon [1]. It is a generally recognized as safe (GRAS) molecule approved for use in foods by the Food and Drug Administration (FDA). The U. S. Flavoring Extract Manufacturers’ Association reported that TC has a wide margin of safety between conservative estimates of intake and no observed adverse effect levels, from sub-chronic and chronic studies [1]. The report also indicated no genotoxic or mutagenic effects due to TC. Although, cinnamon or cinnamon oil has been used for ages in the treatment of UTIs, no scientific study was undertaken to investigate its antimicrobial efficacy against uropathogens. Amalaradjou and group [2010; 4] investigated the efficacy of TC for controlling UPEC biofilm formation. They observed that TC as a catheter lock solution or as a coating significantly inactivated UPEC and prevented biofilm formation when compared to untreated catheters. In a follow up study, these researchers reported that TC decreased the attachment and invasion of UPEC in cultured urinary tract epithelial cells by down-regulating several virulence genes in the pathogen [5].

Besides the use of cranberry and TC, other plant derived natural antimicrobials have also been shown to be effective against uropathogens. Sosa and Zunino [2009; 141] demonstrated that Ibicella lutea (Devils claw or Rams horn) extracts had an effect on bacterial growth rate and morphology of P.mirabilis by affecting its swarming differentiation, hemagglutination and biofilm formation on glass and polystyrene. Similarly, the use of Coccinia grandis (Ivy gourd) plant extracts have been reported to inhibit growth of UPEC in vitro [119]. Several other herbs that are used for the treatment of UTIs, but lacking scientific basis include Agrimonia eupatoria (agrimony), Althea officinalis (marshmallow), Apium graveolens (celery seed), Arctium lappa (burdock), Elymus repens (couchgrass), Hydrangea aborescens (hydrangea), Juniperus communis (juniper), Mentha piperita (peppermint), Taraxacum officinalis leaf (dandelion), Ulmus fulva (slippery elm) and Zea mays (corn silk; 3).

#### 5.5.4. Silver coated catheters

Silver is a well-known antimicrobial exerting its bactericidal action by inactivating bacterial enzymes and causing cell wall damage [96]. Silver alloy and silver oxide coatings on catheters were investigated for reducing CAB, where silver alloy coating was found to be more effective [131]. In addition to reducing CAB, other studies also demonstrated the ability of silver alloy to decrease CAUTI compared to silver oxide or latex catheters [143]. However other researchers have observed conflicting results with no difference in antibiofilm effect of silver alloy and silver oxide [122, 143].

### 5.6. Enzyme inhibitors

Urease producing bacteria are known to produce crystalline biofilms and encrustation on catheters. Use of urease inhibitors such as acetohydroxamic acid and fluorofamide have been reported to reduce encrustation and thereby prevent CAB [98]. These urease inhibitors have been also shown to prevent urea break down and pH increase in vitro by P. mirabilis besides decreasing the associated encrustation. Another enzyme target is N-acetyl-D-glucosamine-1-phosphate acetyltransferase, which is essential for peptidoglycan, lipopolysaccharide and adhesion synthesis. Inhibitors of the enzyme belonging to the N-substituted maleimide family have produced antibiofilm activity against P. aeruginosa and S. epidermidis compared to silver hydrogel coated catheters [17].

#### 5.6.1. Bacterial interference

Use of nonpathogenic microorganisms to counteract pathogenic bacteria is known as bacterial interference [137]. Colonization of catheter surfaces with nonpathogenic bacteria can prevent adhesion and colonization by pathogens. The nonpathogenic E. coli 83972 has been extensively investigated both in vitro and in vivo in bacterial interference protocols [68]. Initially, studies with this nonpathogenic strain were done by instilling the bacteria into the bladder of patients. Colonization by E. coli 83972 protected these patients from symptomatic UTI. To reduce the need for instillation of bacteria into the bladder of patients, experiments were later conducted with catheters coated with the nonpathogenic strain [168]. This study also revealed that E. coli 83972 was effective in reducing symptomatic UTI similar to previous experiments with direct infusion of the bacteria.

#### 5.6.2. Bacteriophages

Another potential approach investigated for controlling CAUTI is the use of bacteriophages. Catheters coated with T4 bacteriophage against E. coli and coli-proteus bacteriophage active against Proteus were exposed to E. coli ATCC 11303, P. mirabilis or saline. It was observed that phage treatment of catheters led to approximately 90% reduction in biofilm formation compared to control catheters [19]. It was also observed that the application of phage cocktail on catheters was more effective against bacteria than the use of a single phage [19]. When hydrogel coated catheters were pretreated with a five-phage cocktail, P. aeruginosa biofilm formation was reduced by 99% after 48 h [45].

#### 5.6.3. Liposomes

Liposomes are carrier or delivery vehicles that can carry both hydrophilic and hydrophobic molecules to their target site for delivery. This helps to increase the half life of the drugs besides protecting them from the environment. Liposomes containing ciprofloxacin embedded in a hydrogel coated catheter were evaluated in a rabbit model to investigate its antibiofilm effect against E. coli induced CAUTI [121]. The results from this study revealed that liposomal ciprofloxacin treated group had a delayed onset of positive urine cultures compared to the control group.

#### 5.6.4. Quorum sensing inhibitors

Quorum sensing between bacterial cells in a biofilm have been shown to be essential for biofilm formation and maintenance. Inhibition of quorum sensing could therefore provide a potential route for the control of biofilms. Delisea pulchra, an algal species has been shown to produce furanones that interfere with autoinducer signaling and biofilm formation [92]. In vitro and in vivo sheep experiments using furanone containing catheters have been evaluated against S. epidermidis [35]. Similarly, use of azithromycin has been shown to inhibit the production of quorum sensing signals, swimming, swarming and twitching motilities, and biofilm formation in vitro [9].

#### 5.6.5. Surface vibroacoustic stimulation

Catheters containing peizo elements can generate low energy acoustic waves that can lead to the formation of a vibrating coat along the catheter and prevent bacterial attachment and biofilm formation [60]. Scanning electron microscopy studies demonstrated that application of surface acoustic waves led to reduced biofilm formation by E. coli, E. faecalis, Candida albicans and P. mirabilis. An in vivo study in rabbits demonstrated that peizo element containing catheters with acoustic vibration led to a delayed positive urine culture compared to control animals [60]. The acoustic waves generated resulted in bacterial vibration at the same frequency, thereby preventing bacterial attachment and eventual biofilm formation.

## 6. Conclusion

Catheter associated urinary tract infections are the most common nosocomial infections and a vast majority of them are caused by biofilms formed on catheters. The complications caused by biofilms can undermine the patient’s quality of life and threaten their health. The high incidence of CAUTI and the consequent complications warrants the development and application of effective control strategies. Prevention is predominantly based on enforcing guidelines for appropriate catheter placement and early removal. However, a comprehensive understanding of bacterial biofilm formation, pathogenesis and other key factors essential for development of UTIs would help in the development of novel and effective control strategies.

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© 2013 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Mary Anne Roshni Amalaradjou and Kumar Venkitanarayanan (July 10th 2013). Role of Bacterial Biofilms in Catheter-Associated Urinary Tract Infections (CAUTI) and Strategies for Their Control, Recent Advances in the Field of Urinary Tract Infections, Thomas Nelius, IntechOpen, DOI: 10.5772/55200. Available from:

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