Nanodiamonds (ND) are carbon-based nanoparticles that have been studied as promising candidates for drug delivery. In general, carbon nanomaterials exert their antibacterial activity by direct interaction between their surface chemical groups and the bacterial wall, thereby inducing physical damage and metabolism inhibition. Interestingly, NDs enhance these antibacterial properties due to their physical and chemical characteristics such as small size, diverse and adjustable surface functionalization, chemically inert core, and their capability to be internalized into mammalian cells (Faklaris et al., 2008). Moreover, NDs are biocompatible and less cytotoxic in comparison to other carbon-based NPs, acquiring more importance in biomedicine (Zhu et al., 2012) ( Table 2 ). To support this hypothesis, Beranová et al. evaluated the antibacterial effect of NDs against E. coli, showing that NDs exerted antibacterial activity in a concentration dependent manner (5 µg/mL inhibited 25% of bacteria growth, while 50 µg/mL or more inhibited bacteria growth completely). The authors concluded that the bactericidal effect may have been due to the clustering of NDs around bacteria, which would probably interrupt essential cellular functions (Beranová et al., 2012).

On the other hand, Iyer et al. evaluated the ability of two different sizes of NDs (6 and 25 nm NDS) for being endocytosed into human bladder cells and kill intracellular UPEC, using T24 bladder cells infected by an invasive UPEC strain. Infected cells were then treated during two hours with 200 µg/mL of NDs. The results indicated that 6 nm NDs displayed better antibacterial effects on UPEC than acid-treated 25 nm NDs. Internalization assays were performed in the same cells using transmission electronic microscopy (TEM). Microscopy images showed that acid-treated 6 and 25 nm NDs were associated and internalized into bladder cells suggesting their utility against UPEC (Iyer et al., 2018). In this research area, Khanal et al. have developed trimeric thiomannoside clusters conjugated to NDs (ND-Man3) as anti-adhesive nanoparticles. The aim of ND-Man3 was targeting E. coli type-1 fimbriae, its major virulence factor. The efficiency of the ND-Man3 to inhibit bacterial adhesion to cell surfaces mediated by type 1 fimbriae was evaluated with two different assays: the inhibition of yeast agglutination; and inhibition of bacterial adhesion on the T24 bladder cells. The inhibition of yeast agglutination assay evaluates the capacity of E. coli type 1 fimbriae to recognize mannosylated residues on yeast surface, which is visualized by their aggregation in positive samples. The results revealed ND-Man3 inhibited the adhesion of bacteria to yeast cells 91 times more than unconjugated NDs. In addition, in the case of the bacterial binding to T24 bladder cell inhibition assay, the authors tested the ability of ND-Man3 to interfere with bacterial FimH-mediated recognition of T24 cells. The results showed that ND-Man3 inhibited adherence to T24 cells 133 times more than unconjugated NDs (Khanal et al., 2015).

Considering the aforementioned, NDs intrinsic antimicrobial properties are a promising approach for UTI management, since they have showed to be effective in the elimination not only of the extracellular bacteria, but also intracellular. This characteristic is very important because urinary tract pathogens like UPEC can invade host cytosol and exponentially grow there, forming biofilm-like inclusions called intracellular bacteria communities (IBC) (Anderson et al., 2003; Conover et al., 2016). These IBC cause chronic and recurrent infections and are very difficult to eliminate due to the inability of many antibiotics to cross cell membranes (Maurin and Raoult, 2001; Anderson et al., 2003). Hence, the use of NDs as antimicrobials would overcome classic antibiotics limitations.

The presented studies show the potential of organic nanoparticles as carriers, adjuvants, or drugs in UTI treatment. They highlight their use as coating materials for different urinary tract devices (Fong et al., 2010; Beranová et al., 2012; Khanal et al., 2015; Phuengkham and Nasongkla, 2015; Francesko et al., 2016; Venkat Kumar et al., 2016; Macedo et al., 2017; Ludwig et al., 2018; Lopes et al., 2019; Srisang and Nasongkla, 2019). Thus, this kind of therapy would be destined specifically to hospitalized and catheterized patients. Among this research the studies conducted by Fong et al. and Venkat et al. standout due to their in vitro drug release experiments. Thereby showing the possible behavior these NPs would have inside the body when used as catheters coating to prevent and avoid CAUTIs. Furthermore, the use of intravaginal administration of nanoemulsions based on natural compounds is one of the most promising alternatives to improve the actual treatment against UTIs (Kaur et al., 2017a; Kaur et al., 2017b; Atinderpal et al., 2018). This is due to natural compounds’ benefits for human health and their biocompatibility, in addition to the inherent benefit that a local administration represents. It is important to emphasize that these studies that propose the intravaginal administration route are the only ones that analyzed in vitro and in vivo pharmacokinetics parameters making this administration route the most suitable used in the treatment of UTIs in women. Another strategy to achieve local administration of nanoparticles is the injection directly into the bladder, as suggested by Lui et al. (2015), Iyer et al. (2018) and Khanal et al. (2015). In that context, it is noteworthy that in all previous cases a local administration route is preferred for the treatment of UTIs with nanoparticles, either by intravaginal or intravesical route for both, inpatients and outpatients. Moreover, the use of nanosystems capable of inactivating or killing urinary tract pathogens as catheters coating would prevent CAUTIs and reduce the formations of biofilms. In addition, vaccination is gaining importance in the search for a novel strategy towards UTIs prevention, as shown by the results obtained by Crecente et al. using subcutaneous vaccines for the reduction of the increasing number of UTI and CAUTI and the prevention of antibiotic resistance (Crecente-Campo et al., 2018).

Silver is recognized as a promising strategy against microorganisms, since it disrupts both, cell wall and metabolic pathways (Sim et al., 2018). The use of silver-based nanosystems to treat UTIs has been studied isolated and in combination with other materials ( Table 3 ). For example, Syed et al. assessed the antibacterial effect of silver nanoparticles (AgNps) against E. coli and S. aureus isolated from CAUTI patients. In this investigation, the bactericidal potential of AgNps was assessed by direct colony count. The number of viable bacteria was measured after the exposure of 10⁵ CFU/mL to different concentrations of AgNPs suspension (0, 10, 50, and 100 μg/mL) after 24 hours of incubation. Results showed that AgNps reduce the number of viable cells for both, E. coli and S. aureus, in a concentration dependent manner (Syed et al., 2009). On another research, El-Batal et al., developed silver-boron nanoparticles (AgB-NPs) and evaluated their antimicrobial activities against MDR urinary tract pathogens. These AgB-NPs had a MIC of 3.90 µg/ml against E. coli, 7.81 µg/ml against S. aureus, and 1.95 µg/ml against C. albicans. After 24 h of incubation, through the agar-disc diffusion test, the zone of inhibition revealed that AgB-NPs were effective as antimicrobials at a concentration of 25 µg/ml. The best action was displayed against E. coli (18.0 mm ZOI) and S. aureus (16.0 mm ZOI); additionally, they exhibited effective antifungal effects, with great potency against C. albicans and C. tropicalis (20.0 mm and 15.0 mm ZOI, respectively) (El-Batal et al., 2019). Another investigation explored the development of Ag/ZnO nanoparticles alone and in combination with ciprofloxacin and assessed their efficacy against an E. coli-induced UTI rat model. These Ag/ZnO NPs exerted a MIC and minimum bactericidal concentration (MBC) of 32 µg/mL and 512 µg/mL, respectively. Additionally, the use of the 512 µg/mL Ag/ZnO NPs in combination with ciprofloxacin reduced the severity of renal cortical thickness of pyelonephritic rats (Khoshkbejari et al., 2015). In a different study, the authors investigated the synergism between AgNPs and antibiotics against MDR uropathogens (E. faecium, S. aureus, A. baumannii, E. cloacae, three different isolates of E. coli, K. pneumoniae, M. morganii and P. aeruginosa). Ampicillin (AMP) and amikacin (AMK) were assessed alone and in combinations with AgNPs against the MDR clinical strains isolated from CAUTI patients. All clinical isolates showed a MIC between 4-16 µg/mL and 4–128 µg/mL to AgNPs and amikacin, respectively, while all Gram-negative strains resulted to be ampicillin resistant. The combinations of AgNPs + AMK showed a synergistic effect reducing the MIC by 2 to 32-fold. On the other hand, AgNps + AMP reduced S. aureus and E. cloacae MICs by 1- and 4-fold respectively (Lopez-Carrizales et al., 2018). In another research looking into optimizing the antibacterial and antibiofilm properties of AgNPs, Bhargava et al. developed L-fucose-functionalized nanoparticles (FNPs). The aim was to increase FNPs interactions with P. aeruginosa PAO1 using LecB lectins present on the bacteria. They compared them to similar size and concentration of citrate capped silver nanoparticles (CNPs). The authors observed that, by measuring the MBC in static conditions, only 40 µg (Ag)/mL in FNPs aliquots were required to kill all bacteria in comparison with CNPs, which required 70 µg (Ag)/mL (Bhargava et al., 2018),. In another attempt to synergistically increase the therapeutic efficacy of silver nanoclusters (NCls), branched polyethylenimine (bPEI) and silver were combined in the synthesis of bPEI-coated blue fluorescent cationic silver nanoclusters (bPEI−Ag-NCls). bPEI is an effective transfection reagent widely investigated as a non-viral vector for DNA delivery (Kunath et al., 2003). The antibacterial ability of these NCls was evaluated against twelve MDR uropathogenic strains by determining MIC through the broth dilution method. AgNO3 and PEI were used as controls. The results showed that bPEI-Ag NCls had a 2-to 3-fold lower MIC than AgNO3 and 10- to 15-fold lower MIC than that PEI. In addition, in hemolysis assays and fibroblasts cultures, it was additionally shown that these bPEI-Ag NCls had a selective cytotoxicity against bacteria, and were biocompatible with human fibroblasts and red blood cells (Huma et al., 2018).

Silver was widely used as antibacterial agent in the 19^th century, until the discovery of the new antibiotics in the early 20^th century (Möhler et al., 2018; Sim et al., 2018). However, bacteria have progressively developed different mechanism to evade antibiotic effects (Möhler et al., 2018; Sim et al., 2018). Nowadays, the fight against infections like UTI caused by MDR pathogens represents a challenge. So, to overcome antibiotics resistance, silver is being reconsidered as antimicrobial agent. But now, the use of silver is studied in a more refined manner using strategies such as nanotechnology. AgNPs are already being used for catheter coating to prevent CAUTI due to their antimicrobial and antibiofilm potential. However, their ability to be combined or functionalized increases the interest in the use silver-based NPs to develop powerful molecules for UTI treatment, one of the most MDR pathogens-associated infections.

Because of its biocide nature and its antibacterial ability reported since Egyptian medical texts (Nunn, 2002), copper (Cu) is another common metal widely used for the synthesis of nanoparticles as nanoantibiotics, having the advantage of its lower cost in comparison with silver (Rane et al., 2018). The utility of Cu against uropathogens is principally as antibiofilm agent to prevent CAUTI ( Table 5 ). To amplify this concept Shalom et al. coated urinary silicone catheters with Zn-doped CuO nanoparticles. Subsequently, their antibiofilm activity was evaluated against E. coli, S. aureus, and P. mirabilis, observing a biofilm persistence of 9, 8% and 0.5%, respectively. Finally, the authors performed experiments using rabbits as an in vivo model to which coated and uncoated catheters were applied. Rabbits catheterized with uncoated catheters developed CAUTI at day 4 of the experiment. In contrast, CAUTI was not diagnosed in rabbits catheterized with coated catheters during the time that the experiment was performed (7 days) (Shalom et al., 2017).

In another study, researchers evaluated the antibiofilm activity of commercial CuO NPs against biofilm formed from methicillin-resistant Staphylococcus aureus (MRSA) and E. coli. First, Agarwale et al., determined a 30 μg/mL and 35 μg/mL CuO NPs-MIC, for MRSA and for E. coli, respectively. Next, they assessed the antibiofilm activity of CuO NPs employing sub-MIC concentrations. Results indicated that CuO NPs completely inhibited biofilm formation at a concentration from 2MIC to ½MIC, while lower concentrations did not inhibit the biofilm completely (Agarwala et al., 2014).

The aforementioned exposed that Cu used into NPs reduces biofilm formation efficiently, which is associated to the damage that Cu produces in microorganisms, since it destroys microorganism’s envelope and nucleic acids leading to cell death (Rane et al., 2018). These Cu properties added to nanotechnology strategies, present Cu-based NPs as excellent candidates for their inclusion in CAUTI prevention treatments. Furthermore, the inclusion of NPs onto catheters surface reduces biodistribution and bioavailability problems, thus representing a big advantage for their future biomedical approval and commercialization.

Other metal with antibacterial properties used for NPs synthesis is zinc, which has potential to achieve more effective UTI treatments ( Table 7 ). Zinc oxide nanoparticles (ZnO NPs) have been developed by two different methods (green and conventional chemical syntheses). The antibacterial ability of these NPs was evaluated against carbapenem-resistant RS307 strain of Acinetobacter baumannii, an opportunistic pathogen of urinary tract. Growth kinetics assay showed that the growth of A. baumannii were inhibited by chemically ZnO NPs more than by green synthesized ZnONPs. This effect was attributed to the ROS production by the chemically synthesized NPs (Tiwari et al., 2018). In other research, authors investigated the capacity of ZnO NPs to reduce both biofilm formation and antigen 43 (Ag43) expressions in UPEC CFT073. Ag43 is an important surface adhesin encoded by the E. coli-flu gene (Zalewska-Pia Tek et al., 2015). E. coli surface also presents the Ag43 receptor, which mediates bacteria-bacteria adherence, favoring their auto-aggregation, essential for the biofilm formation (Ulett et al., 2007). The ZnO NPs MIC was determined against UPEC isolated from urine samples of inpatients and outpatients, using the agar diffusion methods and different NPs concentrations. Some isolated bacteria resulted to be ESBL-positive, thus resistant to third generation cephalosporins. The MIC obtained for no ESBL-producing E. coli was 2971 µg/mL, while for ESBL-producing E. coli the MIC was 3541 µg/ml. With the MIC concentration, they measured the antibiofilm activity of the ZnO NPs by microtiter plate assay. For that, they first measured the extend of biofilm by optical density (OD₄₉₀), considering values of ˂0.1, 0.1-0.2, 0.2-0.3, and ˃0.3, representing non, weak, moderate, and strong biofilm former respectively (Naves et al., 2008). They determined that the biofilm formation was fully inhibited in about 20% of isolates with strong biofilm formation, 14% in moderates, and 16% in weaks. Finally, they assessed the level of the flu gene expression by Real-Time PCR assay, determining that ½MIC concentration of NPs significantly reduced the flu gene expression in these bacteria (Shakerimoghaddam et al., 2017). Hence, they found a direct correlation between biofilm strength and flu gene expression. Other authors have developed Magnesium-doped zinc oxide nanoparticles (ZnO : MgO NPs), and evaluated their antibiofilm activity against CAUTI-isolated P. mirabilis. To evaluate the effect of ZnO : MgO NPs over P. mirabilis biofilm, they covered glass coverslips with polymer and nanoparticle dispersion containing 1% of HPMC and different percentages of ZnO : MgO NPs (0.0004, 0.0011, 0.0023 and 0.0053% w/w). They used glass coverslip with and without 1% HPMC as controls. Then, coated coverslips were incubated with P. mirabilis culture for 7 days. Coverslips were then subjected to immunofluorescence staining and confocal microscopy image acquisition. Deep image analysis and mathematical morpho-topological descriptors (bacterial volume, and number, and extracellular volume) revealed that each NPs concentration induced a different biofilm behavior. The best concentration of these NPs to inhibit biofilm formation was 0.0011% w/w, maintaining the smallest morpho-topological parameters values during all assays compared to controls and the other NPs concentrations (Iribarnegaray et al., 2019). In a different study, Hosseine et al. evaluated the ZnO NPs effect on agglutinin-like sequence (ALS) 1 and ALS3 gene expression. ALS are proteins present in cells surface of C. albicans with a key role in biofilm formation, especially ALS3 (Nailis et al., 2010). The antifungal effect of ZnO NPs was carried out by MIC determination against patients-isolated C. albicans strains. The results of MIC determinations showed that all strains were sensitive to ZnO NPs at a concentration of 17.76 µg/mL. Then authors analyzed the effect of ZnO NPs on the expression of ALS genes by Real-Time PCR. For that, they treated C. albicans strains with a sub-MIC concentration of ZnO NPs. Results indicated that, after treatment with the sub-MIC concentration of ZnO NPs, the expression of ALS1 and ALS3 decreased significantly, suggesting ZnO NPs as an effective antibiofilm agent (Hosseini et al., 2019). In another investigation, Hosseini et al. studied the influence of ZnO NPs on C. albicans biofilm derived from urinary-catheters isolated strains, some of which were fluconazole resistant. First, the authors determined the MIC of ZnO NPs for all strains obtaining a MIC of 28 µg/mL for fluconazole-susceptible strains and of 47 µg/mL for fluconazole-resistant. Later, the antibiofilm assay showed that concentrations of 29 µg/mL fully inhibited biofilm formation in 80% of susceptible strains and 50 µg/mL inhibited biofilm formation in 100% of resistant strains (Hosseini et al., 2018). On another research, Bhande et al. assessed the synergism between ZnO NPs and beta-lactam antimicrobials (cefotaxime, ampicillin, ceftriaxone and cefepime) against a panel of clinically isolated UTIs ESBL producers (E. coli, P. aeruginosa, S. paucimobilis, and K. pneumoniae). The MIC determination was 80 µg/ml for E. coli, 60 µg/ml for K. pneumoniae, 30 µg/ml for P. aeruginosa, and 50 µg/ml for S. paucimobilis. In addition, time-kill assay by synergistic compound (ZnO NPs + beta-lactam antibiotics) was monitored using broth dilution and agar diffusion method (% fold inhibition) for ESBL producers. Results exposed that both, antibiotics and ZnO NPs delayed the normal pathogens exponential growth. Nevertheless, when they were treated with the different combinations of ZnO NPs + beta-lactam antibiotics, it was observed a sudden impairment in the exponential phase, and a very low stationary phase during the growth transition (Bhande et al., 2013).

Gold-based NPs (AuNPs) ( Table 8 ) have shown potent bactericidal activities by different mechanisms, including membrane damage, protein inactivation and DNA replication inhibition (Cui et al., 2012). For that matter, the antibacterial activity of functionalized AuNPs has been evaluated, using a wide range of different gold-cationic characteristics, such as chain length, non-aromatic, and aromatic properties, for those purposes. The antibacterial activity was first tested on a E. coli laboratory strain (DH5a); using the broth dilution method, the researchers determined that all functionalized AuNPs inhibited E. coli proliferation at nanomolar concentrations. Next, they tested the antibacterial ability of the most potent NPs against E. coli growth. These specific AuNPs carried an n-decan end group (NP3) and inhibited E. coli proliferation at 32 nM (Li et al., 2014). In another study, the authors conjugated AuNPs with chlorhexidine (Au-CHX NPs), where they evaluated the antibacterial and antibiofilm activity against twenty strains of K. pneumoniae isolated from UTI patients and one reference strain (ATCC 13882). The antibacterial effects were investigated by the broth dilution method, while the antibiofilm activity was evaluated by the microtiter plate method. Results revealed that the MIC necessary to inhibit K. pneumoniae ATCC 13882 strain was 25 µM, whereas for all the clinical isolates it was 100-200 µM. Regarding the ability for interrupting the biofilm formation, 25 µM reduced the K. pneumoniae ATCC 13882 strain biofilm to almost 85%, whilst 100 µM were required to reduce the biofilm of clinical isolates to about 90%. It was also determined that concentrations of 100 µM of Au-CHX NPs were able to disrupt the preformed biofilm of all isolates (Ahmed et al., 2016). A different investigation with AuNPs developed silica coated gold nanorods (AuNRs-SiO2) loaded with verteporfin (VP). VP is a photosensitizer, clinically approved as efficient near infrared (NIR) nanostructures for PDT (Turcheniuk et al., 2015). Herein the aim was to use a continuous wave (CW) or a pulsed-mode laser to eliminate E. coli related with UTI. To determine the potential of the AuNR-SiO2–VP as antibacterial photodynamic probe, their bactericidal capacity was assessed under pulsed laser illumination. Using this laser at 710 nm (1 W/cm²), repeated irradiations of AuNR-SiO2–VP, AuNR-SiO2 and VP were applied on E. coli strains. The results showed that E. coli UTI89 was not inactivated at 4 mM neither with AuNR-SiO2 nor VP, while AuNR-SiO2–VP eradicated an infectious dose of 10⁴ CFU/mL of E. coli (Turcheniuk et al., 2015).

Thus, gold nanosystems have great potential for UTI treatment, since they allow the incorporation of other compounds, potentiating their activity using different strategies for bacteria eradication.

Another inorganic molecule used to improve actual UTI treatments is silica, which has been generally used in combination with other materials ( Table 9 ). For example, Tameemi et al. synthesized nanostructures of silica-titanium sieves (Si-Ti-Sv) as nanocarriers for izohidrafural, a new antibacterial agent, obtaining Izo3-Si-Ti-Sv. The antibacterial activity of these nanocarriers was assessed against different bacteria strains of nosocomial UTI pathogens (E. coli, K. pneumoniae, P. mirabilis, M. morganii, and E. faecalis). The results showed Izo3-Si-Ti-Sv had greater antibacterial potential than Si-Ti-Sv and nitrofurantoin. Furthermore, Si-Ti-Sv exposed higher antibacterial activity than nitrofurantoin but lower than Izo3. The authors attributed this synergistic effect to the photolytic properties of titanium dioxide, in the form of anatase, which is present in the hybrid Si-Ti-Sv and generates ROS, thus destroying cells. The increased antimicrobial activity of Izo3, in regard to nitrofurantoin was explained by the isoniazid moiety, a powerful antimicrobial present in the molecular structure of the drug (Al Tameemi et al., 2017). In a different research, the authors conjugated SiO₂ NPS with tannase, an enzyme that catalyzes the hydrolysis of tannic acid ester bonds to produce gallic acid and glucose (Singh et al., 2019). Tannase was obtained and purified from Serratia marcescens. The conjugation was done by feeding and pulse methods (Nsayef Muslim et al., 2017). Then they compare the antibacterial activity of SIO₂ against UTI-related pathogens (S. agalactiae, S. aureus, K. pneumonia, E. coli, P. aeruginosa, E. aerogenes and S. marcescens) with ciprofloxacin, SiO₂ NPs alone, and partially purified tannase. The best results against tested pathogens were achieved with tannase-SiO2 NPs conjugated feeding method (Nsayef Muslim et al., 2017). Mesoporous silica nanoparticles (MSNPs) have also been investigated as part of possible future UTIs treatment because their physical and chemical characteristics are easily modifiable. The ability to alter at will characteristics such as pore size, surface area, stability to organic solvents, biocompatibility, and others, facilitates the incorporation of organic and inorganic particles, thus enhancing antibacterial properties (Stein et al., 2000). Based on this information, mesoporous silica nanoparticles were functionalized with phenazine-1-carboxamide (PCN) (PCN-MSNPs) and used as antimicrobial coating on silicone urethral catheters. Microbial phenazines are nitrogenous aromatic compounds reported to exhibit interesting bioactivities including antimicrobial properties (Shanmugaiah et al., 2010). In this research, the authors evaluated the antifungal activity of PCN-MSNPs against different strains of C. albicans by Minimum Fungicidal Concentration (MFC) assay, in Muller-Hinton Broth (MHB). In this research, it was shown that PCN-MSNPs exhibited a MFC of 7.8-15.6 µg/mL (two-fold lower than PCN) against C. albicans, similar to the standard MZ. The authors also did a polymicrobial inhibition assay using agar well diffusion method against a mixture of C. albicans and S. aureus. The assay revealed that both PCN and PCN-MSNPs inhibited the growth of mixed pathogens, but PCN-MSNPs showed a greater inhibitory effect, which was stable up to 120 hours. Finally, antibiofilm activity of PCN and PCN-MSNPS was assessed against C. albicans and the mixture of C. albicans and S. aureus, in microtiter plates. The results of C. albicans biofilm inhibition assay showed that PCN inhibited the biofilm at a concentration ranging from 80–95 μM, whereas, PCN-MSNPs needed only a dose ranging between 34 to 44 μM. Similar results were found on mixture of pathogens biofilm, where PCN-MSNPs inhibited biofilm formation at a concentration of 53 μM, while PCN showed biofilm inhibition at 105 μM (Kanugala et al., 2019).

A different group of inorganic materials has been employed in the development of nanoparticles to enhance UTI treatments ( Table 10 ). Within this group, hydroxyapatite nanoparticles (nano HA) have been used to develop an antimicrobial coating for urethral catheters with the aim to prevent biofilm formation and CAUTI. In vivo studies in rabbits were conducted with a control catheterized with standard silicon-latex catheters, while the study group received nano-HA coated catheters. To evaluate the biofilm formation on catheters, 1 cm of the distal segment of each catheter was plunged in a transferable culture media and analyzed by scanning electron microscopic (SEM) under 15 kV to determine biofilm thickness. The most frequent bacteria recovered in urine and on the catheter surface in the control group were E. coli, Staphylococcus species, P. mirabilis and E. cloacae. The results showed that at the end of seven days of the catheterization period, the biofilm formation over catheters surface was significantly thinner in the study group, regarding the control group. After the 7 days, the urethra and bladder of each rabbit were excised and analyzed with hematoxylin-eosin. The results indicated that nano-HA coated urethral catheters did not produce histological adverse changes or particle penetration in the urothelium (Evliyaoğlu et al., 2011). In another study, sulfur nanoparticles (SNPs) were green synthesized with Catharanthus roseus leaves extract as reductor agent. The antibacterial efficacy of these SNPs was single evaluated and in combination with antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, gentamicin, imipenem, kanamycin, neomycin, norfloxacin, ofloxacin, trimethoprim) against MDR uropathogens, using disc diffusion method against uropathogenic bacteria isolated from 351 human urine samples. The isolated pathogens were E. coli, P. mirabilis, P. aeruginosa, K. pneumoniae, E. faecalis and S. aureus. The results showed that SNPs alone or combined with antibiotics had inhibition activity against all assessed pathogens, being 14.66 mm the maximum ZOI observed for SNPs-Amoxicillin combination against E. coli (Paralikar et al., 2019). In yet another example, tungsten nanoparticles (WNPs) were assessed against biofilm formation from CAUTI patients isolated E. coli strains. Antibacterial properties were assessed against these bacteria and against (S. aureus) reference strain (ATCC 6538). To measure the antibacterial potential of these novel WNPs authors applied MIC determination and the results revealed that while 6000 µg/mL of cefotaxime were necessary to inhibit E. coli growth and 2000 µg/mL were needed to avoid S. aureus growth, only 1500 µg/mL of WNPs were enough to avoid E. coli and S. aureus growth (Syed et al., 2010). Finally, nickel oxide nanoparticles (NiO NPs) are one of the most promising metal oxides used for biomedicine and drug delivery applications (Bano et al., 2016; Kganyago et al., 2018). Pure NiO NPs and Nd³⁺ doped NiO NPs (Nd-NiO NPs) antibacterial have been tested, in comparison to commercial antibiotic treatment (erythromycin). The antibacterial ability of NPs was measured by the well diffusion method against P. mirabilis. Results indicated that NiO and Nd-NiO NPs possessed greater antimicrobial activity than erythromycin, mainly due to Ni²⁺ positive charge, which is released when NiO interacts with the negative charges present on microbe cell membranes. Ni²⁺ is internalized into the cell membrane and reacts with sulfhydryl groups. Therefore, the activity of synthetase in the microorganism becomes disrupted, thus the cellulose grows through cell division, which in turn leads to microbe death (Rahman et al., 2018).

After the analysis of the reported studies, it becomes evident that the most explored inorganic nanoparticles for UTI treatment are silver-based nanoparticles, alone or in combination with other materials. In this context, the extensive investigation of AgNPs is due to their antimicrobial properties and their ability to combat human pathogen has been showed constantly over the years. The importance of silver in UTI treatment is reflected in its actual use as catheters coating to prevent nosocomial microbial contamination and reduce UTIs as a secondary effect (Politano et al., 2013). Other metals like copper, zinc, gold, and silica share these antimicrobial characteristics with silver, but despite they effectiveness, they have not been approved for human or animal use yet. Other inorganic materials have been also evaluated but with less intensity, which can be related to the difficulty for their approval for human use and thus, their introduction as clinical treatments. Nevertheless, green synthesis is gaining more relevance due to the greater biological and environmental compatibility of these NPs.

Nowadays, inorganic NPs are widely considered as catheters coating, among which AgNPs are already being used to prevent catheter bacterial colonization, while other inorganic materials are currently under investigation. All reported inorganic compounds-based NPs as well as organic NPs, show a tendency to be include in urinary tract devices to prevent biofilm formation and reduce CAUTIs (Meenakumari et al., 2000; Ulett et al., 2007; Syed et al., 2009; Syed et al., 2010; Evliyaoğlu et al., 2011; Agarwala et al., 2014; Prabha et al., 2014; Ahmed et al., 2016; Shafreen et al., 2017; Shalom et al., 2017; Bhargava et al., 2018; Hosseini et al., 2018; Rajivgandhi et al., 2018; Divya et al., 2019; Iribarnegaray et al., 2019; Hosseini et al., 2019; Kanugala et al., 2019). Furthermore, some investigations have exposed that their synthetized NPs could have the potential to be used either as a catheter coating or as a systemic administration drug. However, they need to expand their in vitro and in vivo evidence for their approval for their clinical use as UTIs treatment (Sivaraj et al., 2014; Li et al., 2014; Qasim et al., 2015; Turcheniuk et al., 2015; Malarkodi and Rajeshkumar, 2017; Al Tameemi et al., 2017; Nsayef Muslim et al., 2017; Lopez-Carrizales et al., 2018; Mishra and Padhy, 2018; Rahman et al., 2018; Tiwari et al., 2018; El-Batal et al., 2019; Rajivgandhi et al., 2019). Other inorganic NPs have also shown a great potential like adjuvants in combination therapy with antibiotics (Bhande et al., 2013; Paralikar et al., 2019). In addition, inorganic NPs are even under the scope as potential systemic therapies for UTI (Huma et al., 2018) (Khoshkbejari et al., 2015).

Because of the high resistance that urinary tract pathogens have developed to antibiotics, the development of new effective and potent antimicrobial agents is urgently needed. In this context, composite materials have emerged as novel strategies designed to treat UTIs ( Table 11 ). Metal-organic frameworks (MOFs), are organic-inorganic hybrid porous nanostructures, that have been developed to treat infections, since they have the capacity to act as antimicrobial materials, as well as drug carriers (Férey, 2008). The potential of MOFs to combat MDR pathogens is based on the possibility to incorporate different kind of particles into MOFs pores, their metal component, and in their ability to produce physical damage to microbial cells (Wyszogrodzka et al., 2016). In this context, a ZnO-ZIF-8 nanocomposite was evaluated as an antibiofilm agent against four common uropathogens (E. coli, K. pneumoniae, P. mirabilis, and S. aureus). ZIF-8 is a zeolitic imidazolate framework useful for drug delivery, since its porous features, and for being thermally and chemically stable, and modifiable and pH sensitive (Kaur H et al., 2017). With the MBC assay it was determined that 0.25 µg/mL of ZnO-ZIF-8 compound was able to kill all four microorganisms. The antibiofilm effect was demonstrated by the capability of 2 µg/mL suspensions of ZnO-ZIF-8 to diminish well-established biofilms formed from concentrations of 10⁷-10⁹ CFU/mL to below the limit of detection (BLD). The ZnO-ZIF-8 showed a reduction of 6-8 log, when compared to the control solution, over a 24 h period. Finally, authors of this research prepared ZnO-ZIF-8 embedded silicone elastomers with 2 or 4 w/w % and observed that they effectively eliminated all four microorganisms from the surface after 24 h of exposition, showing their utility to prevent CAUTI (Redfern et al., 2018).

In a different research a silver-polytetrafluoroethylene (Ag-PTFE) nanocomposite coating for urinary catheter was developed, with the aim to obtain a synergistic effect between the antibacterial activity of silver and the antiadhesive activity of PTFE. The antibacterial and antiadhesive abilities of these coated catheters were evaluated against two of the most common uropathogens (E. coli and S. aureus). The anti-adhesion efficacy of Ag-PTFE composite was analyzed by fluorescence microscopy in uncoated, Ag-coated, and Ag-PTFE-coated catheters, determining that Ag-PTFE-coated catheters reduced 55.2-60.3% of E. coli adhesion and 49.1-56.5% of S. aureus adhesion compared to uncoated and Ag coated catheters, respectively. The antibiofilm ability of the Ag-PTFE-coated catheters was investigated and compared with BARD PTFE-coated Foley catheters and Mediplus all-silicone Foley catheters through a prolonged culturing of 48 hours prior to SEM observation. The SEM results showed that Ag-PTFE-coated catheters diminished the 95.2% biofilm coverage of E. coli and the 96.2-97.4% of S. aureus biofilm in contrast to the uncoated and PTFE-coated catheters. In addition, with an in vitro bladder model authors observed that the Ag-PTFE coated catheters exhibited great anti-infection efficacy against bacteriuria, thus prolonging silicone catheters lifetime from a mean of 6 days to 40 days making these Ag-PTFE coated catheters good candidates to avoid CAUTI (Zhang et al., 2019).

In other investigation the authors synthesized a new nanocomposite formed by hydrogel and copper NPs (HCuNPs). The antibacterial potential of HcuNPs was assessed against E. coli, K. pneumoniae, P. aeruginosa, P. vulgaris, S. aureus and P. mirabilis strains collected from infected urine samples. To measure HCuNPs and hydrogel antibacterial activity, they applied the agar disc diffusion method. The results indicated that HCuNPs had a superior biocidal activity than parenteral hydrogel in similar conditions giving a ZOIs higher than 16 mm for all the pathogens at a concentration of 5 mg/mL (Al-Enizi et al., 2018).

Dayyoub et al., developed tetraether lipids (TEL)-coated silver nanoparticles distributed in a hydrophobic PLGA film loaded with norfloxacin. TEL are a fundamental part of cell membrane of the archaeon Thermoplasma acidophilum; due to the absence of cell wall on the archaeon, TEL are the responsible to provide high thermal and chemical stability (Boyd et al., 2013). These lipids are bound to the glycerol residues by ether bonds, not having double bonds; the latter characteristic provides long-term resistance against biochemical degradation, and oxidative and hydrolytic agents, making these lipids suitable candidates to be used in urinary tract conditions (Dayyoub et al., 2008). In this context, polyurethane (PUR) and silicone sheets have been coated with the polymer films loaded with the antibacterial agents. The antibacterial and anti-encrustation assays were performed using an in vitro model of UTI cultures of S. aureus, S. epidermidis, E. coli, E. faecalis and P. aeruginosa, all of which were cultivated in artificial urine. The results showed that films with TEL-coated Ag NPs effectively inhibited the in vitro adhesion of bacteria in about 83%, compared to uncoated sheets (inhibition potential of 48%.) These results were confirmed by scanning fluorescence microscopic images. The results also evidenced that coated films exhibit bactericidal and anti-encrustation effects on their surface (Dayyoub et al., 2017).

In the field of combined materials, silver-bearing degradable polymeric nanoparticles of polyphosphoester-block-poly(L−lactide) were designed for the loading of silver into a hydrophilic shell and/or the hydrophobic core. This “hybrid” delivery system was constructed replacing the polyphosphoester backbone by poly(L-lactide) (PL), a natural lactic acid derived, which is a biocompatible and biodegradable polymer, extensively used for de synthesis of NPs, and possesses high silver loading capacity. Therefore, these NPs were prepared as delivery carriers for Ag-based antimicrobials such as silver acetate (AgOAc) and one of two silver carbene complexes (SCCs). The in vitro antimicrobial ability of Ag-NPs and silver compounds was analyzed by MIC determination against 8 UPEC strains. The results indicated the MIC was improved up to 70% with the packaging of the SCCs in the PL-NP-based delivery system, in comparison with the single SCCs, suggesting Ag-PL-NPs would be beneficial in UTIs treatment (Lim et al., 2015).

Other authors explored the use of Raman-encoded silver-coated gold nanorods (GNRs) as scaffolds to attach glycans and engineer multivalent glycan-functionalized GNRs. The objective of these GNRs was to bind UPEC and eliminate them employing a photothermal effect. The antibacterial assay was carried out against an infectious dose of E. coli (10⁸ CFU/mL), by employing increasing concentrations of GNRs solutions (from 0 to 0.2 nM). Next, E. coli/GNRs dispersions were treated with a NIR laser (808 nm, 1 W/cm²) for 15 minutes. The results revealed that in presence of GNRs, the bacteria were eradicated rapidly, due to the efficient photothermal conversion that NIR generated on GNRs (Mahadevegowda et al., 2018).

As summary, composite materials are developed with the objective to have a synergistic effect between inorganic and organic components, making the combination of these kind of materials into nanocomposites a promising alternative for the prevention of CAUTIs, as well as UTIs treatment. Here, we also showed the tendency to develop NPs as catheters coating (Dayyoub et al., 2017; Redfern et al., 2018; Zhang et al., 2019), along with some studies about innovative methods to design and develop therapy for systemic administration (Mahadevegowda et al., 2018). Also, Lim et al., suggested the use of Ag-PL-NPs by direct inoculation intro de bladder, a tendency shown in other investigators with organic and inorganic NPs, due the advantage that local administration represent (Lim et al., 2015). Interestingly, A-Enizi et al., described an innovative application for their HcuNPs, given their great antimicrobial and absorption properties, suggesting their use in diapers, sanitary towels, menstrual pads, and related products (Al-Enizi et al., 2018).