Bioinspired superhydrophobic urinary catheters were designed using a layer-by-layer deposition technique, an innovative solution to reduce CAUTI The superhydrophobic catheters prevented uropathogenic E. coli WT F1693 and P. mirabilis WT F1697 biofilms under static and dynamic conditions and also delayed encrustation in the catheter lumen (Zhang et al., 2020). The antifouling nature of the superhydrophobic catheter was significant in comparison with other variants of silicone and silver-alloy-hydrogel catheters. Furthermore, Ag nanoparticles were endowed on the superhydrophobic surface to enhance antibacterial efficacy, improve biocompatibility, and reduce bacterial attachment. Several other studies employed a similar approach of spray coating PDMS with trifluoropropyl for catheters to provide a self-cleaning activity that decreased microbial biofilm formation over 14 days (Gayani et al., 2021).

Sharklet AF™, a novel surface technology designed with a sharklet micropattern using a PDMS elastomer (PDMSe), possesses the inherent capacity to prevent colonization, migration, and growth of uropathogenic E. coli (Reddy et al., 2011). Sharklet AF™ PDMSe effectively prevented S. aureus biofilms for 21 days, suggesting that the topographical surface of the catheter did not show evidence of early biofilm colonization (Chung et al., 2007). However, the study must be expanded to a polymicrobial environment and requires pre-clinical evaluation to understand its safety and efficacy in the patients.

Plasma-activated urinary PDMS catheter surfaces were covalently grafted with cellobiose dehydrogenase (CDH), an antimicrobial enzyme that metabolizes oligosaccharides as electron donors to produce hydrogen peroxide in the presence of an electron acceptor (oxygen; O₂). CDH-functionalized PDMS surfaces reduced S. aureus viable cells in the biofilm to >60%; these catheters are biocompatible, as they were non-toxic in mammalian cell lines (Thallinger et al., 2016). Later, an improved PDMS catheter was designed using layer-by-layer assembly in the presence of functional polymeric building blocks. The block consisted of polyanions, poly (styrene sulfonate), and CDH for antibacterial coating as the first layer. The second layer was built using polycations consisting of novel anti-fouling copolymers with zwitterionic and quaternary ammonium side groups (PTMAEMA-co-PSPE). The final layer was laid with sulfobetaine fractions and quaternary hydrophobic groups for contact biocide functionality to reduce the adherence of S. aureus ATCC 10145 by >60%. In addition, the combined antimicrobial coating of the catheter enhanced its killing effect (Vaterrodt et al., 2016).

Silver (Ag), a non-specific antimicrobial, exhibits broad-spectrum antibacterial effects at low concentrations (Zhang et al., 2019). Silver alloy coatings in catheters exist in different forms, such as silver oxide, silver alloys, and silver nanoparticles. Silver alloy releases ions that lead to oxidative DNA damage of pathogens and disrupt the cell membrane (Durán et al., 2016). In addition, silver ions activate vital enzymes that interact with thiol groups and enhance pyrimidine dimerization via a photodynamic approach, causing changes in the cell wall by inducing electron-dense granules (Matsumura et al., 2003). Silver ions are medically important because they are effective against a broad range of bacterial pathogens, specifically methicillin-resistant S. aureus. However, pathogens such as K. pneumoniae, Enterobacter cloacae, P. mirabilis, and C. freundii are emerging as silver-resistant (Estores, 2008). Catheters coated with silver oxide have no market value as they are ineffective in preventing CAUTI (Hooton et al., 2010). Several meta-analyses show that asymptomatic bacteriuria and CAUTI can be effectively reduced using Ag alloy-coated UCs (Ha and Cho, 2006; Hooton et al., 2010; Francolini et al., 2017). Researchers reviewed eight different randomized controlled trials of Ag alloy catheters, confirming their better effects than uncoated catheters; thus, they are recommended for patients at the highest risk of developing severe consequences from UTI (Donlan and William Costerton, 2002). The recommendations were contrary to other research findings; sparfloxacin (SPA)-treated urinary catheters showed better efficacy in inhibiting E. coli and S. aureus growth and biofilm formation relative to Ag-coated catheters (Kowalczuk et al., 2012). Some studies suggest that the Ag alloy-coated catheter delays the onset of infection and does not prevent the occurrence of CAUTI (Zhang et al., 2019).

The drawbacks of silver alloy catheters were addressed by embedding them in a hydrogel to provide a novel hydrogel/silver catheter to prevent CAUTI. The hydrogel/silver catheter efficiently prevented the access of microbes, including gram-positive cocci and yeasts, to the urinary tract extraluminally (Ahearn et al., 2000). A similar study with an Ag-alloy hydrogel-coated catheter was conducted in clinical settings by comparing it with a commercial catheter; a CAUTI rate reduction of 47% was observed (Davenport and Keeley, 2005; Lederer et al., 2014). The Bardex I.C. hydrogel latex Foley catheter, commercially available in the market, has its interior and exterior surfaces lined using a monolayer of Ag, which helps in reducing friction and irritation during catheterization and also provides broad-spectrum antimicrobial protection. (Singha et al., 2017) (C.R. Bard, Inc. 2008-US Patent Application Publication No. US2008/0206943 A1)

Nanoscale materials (nanoparticles; NPs) constitute a broad spectrum of materials, including particulate substances with dimensions <100 nm (Murthy, 2007). NPs can be used as a drug delivery vehicle owing to a high surface area to volume ratio, improved pharmacokinetics and biodistribution, high solubility and stability, and decreased toxicity in comparison to conventional drug delivery systems. Moreover, the physicochemical properties of NPs can be tailored by altering their structural and functional properties to enhance their application potential in the treatment of CAUTI (Din et al., 2017).

Gold nanoparticles (AuNPs) exert bactericidal activity against MDR gram-negative bacteria by collapsing membrane potential or inhibiting protein synthesis (Cui et al., 2012). A study showed that the modification of commercial PVC with methylene blue and 2 nm AuNPs upon exposure to red laser light for 4–8 min increased the photosensitivity of pathogens S. epidermis and E. coli (Noimark et al., 2012). Aegle marmelos leaf extract capped with AuNPs has antimicrobial activity against various biofilm-forming organisms on urinary catheters ( Table 3 ) (Sánchez et al., 2021; Filipović et al., 2022).

Silver-based nanomaterials have gained more attention than AuNPs as well-established (Makabenta et al., 2021) metal antimicrobials that disrupt both bacterial cell walls and metabolic pathways (Sim et al., 2018; Sánchez et al., 2021). Commercial UCs coated with self-polymerized polydopamine act as active platforms for the deposition of silver nanoparticles in situ, preventing biofilm formation by gram-positive bacterial pathogens³⁶. Interestingly, AgNPs exert antibacterial/biofilm and biofilm activities on coagulase-negative S. aureus (Thomas et al., 2015). Foley catheters were coated with AuNPs along with various combinations of antibiotics (amikacin (6.25 µg/mL) and nitrofurantoin (31.25 µg/mL) to observe the combinatorial effect under in vitro and in vivo conditions. These catheters significantly controlled the colonization of microbes until the 14^th day of observation in the mouse model. In addition, the functionalized catheter anti-adherence activity was evaluated two years after storing it aseptically and was proven to be efficient in controlling microbial biofilm >90% ( Table 3 ). Thus, the impregnation of UC with AuNPs and antibiotics is promising for preventing biofilm formation (Mala et al., 2017).

The green synthesis of NPs using biological extracts of lower to higher organisms is safer, non-toxic, biocompatible, and cost-effective (Iravani, 2014; Pal et al., 2019; Sánchez et al., 2021). In this pipeline, green synthesis of AgNPs using the Kocuria rosea strain BS-1 showed antimicrobial and antifouling activity against S. aureus and E. coli. The data was extrapolated toward functionalizing the same (Kocuran-functionalized AgNPs) in urinary silicone catheters, which showed the same response in controlling microbial adherence (Kumar and Sujitha, 2014). Similar studies were conducted in varnishing green AgNPs synthesized using Pistacia lentiscus (mastic), which also prevented bacterial colonization. The AgNPs synthesized using pomegranate grind extract-coated catheters inhibited bacterial colonization for >72 h by antibiotic-resistant clinical gram-positive (S. epidermidis and S. aureus) and gram-negative (E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa) bacteria but were more active against gram-negative bacteria(Goda et al., 2022). Carissa carandas leaf extract-capped silver nanoparticles (AgNPs) coated catheters with commercial antibiotics (ciprofloxacin: 50 mcg, trimethoprim: 30 mcg, and gentamycin: 30 mcg) show antimicrobial and antifouling activities ( Table 3 ) (Rahuman et al., 2021).

Copper nanoparticles affect bacterial cell functions in various ways, adhering to the gram-negative bacterial cell wall via electrostatic force, denaturing the intracellular protein, and further interacting with phosphorus and sulfur-containing molecules, such as DNA (Mahmoodi et al., 2018). A notable added value was observed when hybrid bimetal Cu-Ag NP-coated catheters reduced the viable cell count of E. coli (Andersen and Flores-Mireles, 2019).

Zn-doped CuO (Zn_0.12Cu_0.88O) nanoparticle-coated catheters catheterized in a rabbit model displayed biocompatibility, antibiofilm effects and low cytotoxicity. The nanoparticles, analyzed for seven days, effectively prevented CAUTI. Taken together, these data emphasize the therapeutic potential (antifouling) of Zn-doped CuO nanocomposites (Shalom et al., 2017).

Mesoporous silica nanoparticles (MSNPs) are a class of Food and Drug Administration (FDA)-approved nano-drug delivery systems with the selective advantage of being stable and having customizable pore size, increased surface area, and pore volume, enabling a variety of chemical modifications to improve its functional properties for diagnosis and therapy(Gao et al., 2020). In addition, MSNPs act as both drug carriers and imaging modalities (Farjadian et al., 2019). MSNPs functionalized with phenazine-1-carboxamide (PCN) (PCN-MSNPs) were evaluated against Candida spp. and S. aureus and exhibited a 4-fold increase in antibiofilm activity. These data were incomparable to those of pure PCN. Mechanistic studies showed that PCN-induced intracellular reactive oxygen species accumulation, reduction in membrane permeability and total ergosterol content, and disruption of ionic homeostasis with the release of Na⁺, K⁺, and Ca²⁺ leakage led to the death of C. albicans and S. aureus (Kanugala et al., 2019). Furthermore, a detailed investigation of its efficacy in suitable in vivo models is warranted before clinical application (Farjadian et al., 2019; Gao et al., 2020).

Nanoparticles of tungsten, titanium, sulfur, and hydroxyapatite also show antimicrobial and antifouling activity against uropathogens. Tungsten nanoparticle (W-NP)-coated catheters show bactericidal effects at low concentrations in both clinical and standard drug-resistant pathogenic E. coli (Syed et al., 2010). The green synthesis of sulfur nanoparticles (SNPs) in the presence of Catharanthus roseus leaf extract exhibited antibacterial activity against uropathogens, either alone or in combination with selected antibiotics, such as amoxicillin and trimethoprim (Paralikar et al., 2019). In this pipeline, hydroxyapatite (HA) nanoparticle-coated urethral catheters were tested in rabbit models, and the formation of biofilm on the luminal surface of the catheters was significantly reduced compared to the control until the catheterization period (5–7 days) (Evliyaoğlu et al., 2011).

Polymeric NPs are drug carriers that release antimicrobial agents, bacteriostatic peptides, alkyl pyrimidines, or quaternary ammonium compounds to enable the contact killing of pathogens(Ramasamy and Lee, 2016). A nanoporous polymer film prepared from self-polymerized 1,2-polybutadiene-b-polydimethylsiloxane (1,2-PB-b-PDMS) block copolymers via chemical cross-linking of the 1,2-PB block and sodium dodecyl sulfate blocked E. coli attachment and biofilm for one week. The durability of the activity over seven days was due to the tailoring of the morphological features of the nanoporous polymer films (Li et al., 2013). As a continued effort, researchers devised a catheter material, PDMS, with a known antibacterial component, amino cellulose nanospheres, using epoxy/amine grafting chemistry, which reduced the total biomass in the E. coli biofilms when compared with the naked silicone catheter ( Table 3 ) (Fernandes et al., 2017).

Nitrofurazone, a nitrofuran derivative, is a broad-spectrum antibiotic used to treat UTIs (Lee et al., 2004). It reduces reactive intermediates by releasing nitric oxide (NO), which interferes with ribosomes, DNA, and the cell wall to inhibit bacterial replication, growth, and biofilm formation (Siddiq and Darouiche, 2012; Thompson et al., 2016). Nitrofurazone-coated catheters were tested against a wide spectrum of bacterial pathogens and were found to inhibit the adherence of E. coli and E. faecalis for 3–5 days(Stensballe, 2007; Desai et al., 2010; Kanti et al., 2022). In addition, several other comparative studies showed that the nitrofurazone-impregnated silicone catheter reduced the viable count of E. faecalis and inhibited S. epidermidis and P. aeruginosa biofilms ( Table 3 ) (Kart et al., 2017; Al-Qahtani et al., 2019). However, a nitrofurazone-coated catheter is a promising catheter for preventing bacterial adherence and biofilm; the one that was in commercial use (Rochester Medical Release-NF catheter, USA) was withdrawn from the market as it created discomfort in patients (Zhang et al., 2021). Later, it was listed as prohibited by the FDA because it caused tumors in the animal model subjects (Singha et al., 2017).

Chlorhexidine (N, N‴′1,6-Hexanediylbis[N′-(4-chlorophenyl) (imidodicarbonimidic diamide) is a di-cationic bisbiguanide with broad antibacterial activity (Jones, 1997). To date, research has shown that chlorhexidine is bacteriostatic at low concentrations and vice-versa (bactericidal) in a wide range of gram-positive and gram-negative pathogens (Francolini et al., 2017). The UC is coated with chlorhexidine using either spray or dip coating methods and has potential in appropriate in vitro models that mimic the urinary tract, either alone or in combination with other antimicrobial agents such as triclosan (Kanti et al., 2022). The data showed that chlorhexidine- and triclosan-coated catheters could synergistically prevent the colonization of a wide range of bacterial pathogens for >20 days ( Table 2 )(Anjum et al., 2018). In 2015, polycaprolactone nanospheres loaded with chlorhexidine were spray-coated on silicone catheters to provide a sustained release of chlorohexidine compared to bulk polymers and were effective for 15 days (Phuengkham and Nasongkla, 2015; Singha et al., 2017).

Gendine is an antiseptic dye (gentian violet and chlorhexidine; GND-UC) with broad-spectrum activity against drug-resistant microbes that cause UTIs (Siddiq and Darouiche, 2012). Comparative studies on using GND-UC to other silver hydrogel-coated Foley catheters and uncoated catheters under in vitro conditions suggested that GND-UC is dominant and exhibits better effects against MDR E. coli, P. aeruginosa, ESBL K. pneumoniae, VRE, methicillin-resistant S. aureus, and Candida spp. The extended in vivo study showed similar observations, with a significant decrease in biofilm formation compared to silver-alloy-coated and uncoated catheters (Hachem et al., 2009).

Gentamicin belongs to the class of aminoglycosides known to exert bactericidal effects on a broad range of pathogens, excluding Streptococcus and Enterococcus spp. They exert their action via interacting with the protein synthesizing machinery, specifically the A-site of the 30S ribosome (Krause et al., 2016). To apply gentamicin as a therapy to treat CAUTI, the UCs were coated with this antibiotic with appropriate delivery vehicles known as gentamicin-containing poly (ethylene-co-vinyl acetate) (EVA) and EVA/poly (ethylene oxide) for local and sustained release for a prolonged period of seven days against P. vulgaris, S. aureus and S. epidermis. In vivo, experiments recommend its application to treat short-term catheterization, as it can deteriorate biofilms for 3–5 days (Cho et al., 2003; Ha and Cho, 2006; Rafienia et al., 2013; Roshni et al., 2013; Andersen and Flores-Mireles, 2019). However, studies have shown that when the gentamicin delivery vehicle is changed to PEG, there is a significant change in the release profile, which is extended to 12 days (Rafienia et al., 2013). Although significant results have been obtained, gentamicin-releasing catheters have limitations because gentamicin is a hydrophilic antibiotic known for its rapid release from the carrier; thus, it may not be suitable for short-term catheterization (Ha and Cho, 2006).

Triclosan (TCS) is a synthetic lipid-soluble antimicrobial agent, also known as 5-chloro-2-(2,4-dichloro phenoxy) phenol. It blocks a critical enzyme, enoyl-acyl carrier protein (ACP) reductase (FabI), a critical enzyme that affects the growth of microbes and is involved in fatty acid biosynthesis. In addition, it was observed that the same TCS might also show non-specific actions of targeting multiple pathways and destabilizing membranes (Cadieux et al., 2009; Dhende et al., 2012). However, it is harmless to humans because we lack ENR enzymes (Dhillon et al., 2015). For more than 40 years, it has been used as a disinfectant and preservative in hospitals. Later, it was proposed to have application potential to treat CAUTI via coating in UCs (Yueh and Tukey, 2016). Researchers have conducted detailed investigations of the antimicrobial efficacy of low-density polyethylene (LDPE) catheters with various concentrations of TCS. The addition of TCS (0.5 wt.%) is critical to achieving the minimum inhibitory concentration against multiple uropathogens ( Table 3 ) (Thomé et al., 2012). Several studies have demonstrated the limitation of TCS as pathogens overexpress enoyl reductase or changes in cellular permeability impact its non-functionality for them to develop resistance¹¹². Another study claimed that TCS induces efflux pump overexpression, resulting in high-level resistance in P. aeruginosa (Chuanchuen et al., 2001). Another report suggested that overexpression of the enzyme Fab I by 3–5 fold decreased S. aureus sensitivity against TCS, as mutations were mapped in the gene FabI of resistant strains (Fan et al., 2002). In the year, 2016 the FDA banned TCS in soap products and allowed 1% TCS in toothpaste, mouthwash, and hand sanitizer. In the subsequent year, the European Union banned TCS from all human hygiene biocidal products (Weatherly and Gosse, 2017).

The UC was coated with norfloxacin, a hydrophobic wide-spectrum synthetic antibiotic coated on UC to prevent CAUTI (Park et al., 2003; Ha and Cho, 2006). Norfloxacin was coated on the surface of the catheters with EVA/PEO2kPDMS (poly (ethylene-co-vinyl acetate; EVA), and an amphiphilic multiblock copolymer (poly (ethylene oxide) and poly (dimethyl siloxane); PEO2kPDMS). After coating, norfloxacin release kinetics were established to provide better treatments for patients with long-term catheterization. Experiments showed that EVA/PEO2kPDMS blends containing norfloxacin inhibited selective pathogens (E. coli, K. pneumoniae, and P. vulgaris) over 10 days of treatment. Combinatorial studies of the same blends with norfloxacin and other antibiotics, such as ciprofloxacin and azithromycin, proved to be effective against microbial biofilms; however, further exploration at the preclinical level is warranted (Park et al., 2003; Saini et al., 2016).

Ciprofloxacin (CFX) is an antibacterial agent used to treat a range of infections, including skin, ophthalmic, bone, respiratory, and urinary tract infections (Vidyavathi and Srividya, 2018). A previous study reported that pathogens treated with sub-MIC concentrations of CFX decreased their biofilm, lowering their hydrophobicity (El-Rehewy et al., 2009). Its efficacy over biofilm inhibition expanded its application potential in catheters, and the CFX-coated catheters were evaluated in rabbit models and showed inhibition of E. coli on catheter biofilms (Pugach et al., 1999). Furthermore, a combination of CIP with azithromycin (AZM) showed better efficacy in inhibiting P. aeruginosa (PA01) growth for 30 days, suggesting its stability, shelf life, and future application for the treatment of long-term CAUTI. Further in vivo analysis in the murine model suggests that AZM-CFX-coated catheters were efficient in tackling CAUTI in comparison to the uncoated catheters, which showed persistent colonization of pathogens as well as the dispersion in urine to spread infection further (Saini et al., 2017). In another study, the effects of CFX and N-acetylcysteine-coated catheters, alone and in combination, were evaluated for their antimicrobial adherence activity against various pathogens ( Table 2 ). Ciprofloxacin/N-acetylcysteine-impregnated catheters resulted in the highest inhibitory effect on microbial adherence when compared with controls (85.5%–100%)(El-Rehewy et al., 2009).

Sparfloxacin (SPA)-coated latex catheters were tested against E. coli and S. aureus using broth and agar diffusion methods. The antifouling effect of SPA was compared with that of silver-coated and uncoated catheters. It was observed to significantly reduce the colonization of E. coli and S. aureus compared to both the silver-coated and untreated catheters (Kowalczuk et al., 2012). Furthermore, the same group developed an antimicrobial urological catheter surface modified with a thin film of heparin (HP) deposited with SPA, which was stable to provide long-term antibacterial protection (Kowalczuk et al., 2010).

Although several antibiotics are being explored for use in the treatment of CAUTI, research on other antibiotics is ongoing. The efficacy of the bladder catheter coated with antibiotics (minocycline and rifampin) showed a decrease in the rate of catheter-associated bacteriuria over two weeks compared to that of the control (Darouiche et al., 1999). Meanwhile, the efficacy of third generation cephalosporins, ceftazidime, and ceftriaxone-coated catheters to prevent P. aeruginosa biofilm formation has been investigated. The antibiotics ceftazidime and ceftriaxone delay biofilm formation for more than a week and are recommended for short-term catheterization but not for long-term catheterization (>28 days) (Ghanwate et al. 2014).

Quorum-sensing interaction throws light upon Quorum Quenching, allowing researchers to disrupt bacterial communication and biofilm formation using various modes of action. One possible way to interrupt QS is signal inactivation by enzymatic degradation or modification. This led to the discovery of quorum-quenching enzymes, such as acylase and amylase (Fetzner, 2015; Murugayah and Gerth, 2019). Multilayer UC coatings with either acylase or amylase suppressed the biofilm formation of P. aeruginosa and S. aureus. In a recent study, hybrid nanocoatings with QS-signal-degrading acylase enhanced biofilm inhibition of clinically relevant bacterial pathogens in both mono and mixed species in static and dynamic conditions. Moreover, quorum quenching, and matrix-degrading enzymes offset the growth of biofilms for up to seven days in an in vivo animal model (Ivanova et al., 2015). In addition, lactonases produced by Bacillus thuringiensis (AiiA), archaeon Sulfolobus solfataricus(SsoPox) hydrolysis the AHL’s secreted by the pathogen to protect themselves could also be tested as a potential catheter coating to prevent degrade QS signal and inhibit biofilm formation(Rémy et al., 2016; Bzdrenga et al., 2017).