**3. Biofilm formation by UPEC**

Currently biofilm is defined as a structured bacterial community embedded in a self-produced matrix and attached to an abiotic or living surface [49].

The biofilm matrix is composed with exopolysaccharides, which form a hydrated viscous layer and protects enclosed bacterial cells against dehydration, toxic molecules such as antibiotics, and from immune system of host [50]. Bacteria within the biofilm differ in gene expression resulting in a phenotype different from the planktonic bacteria. The slow growth of pathogens in biofilms is the major factor conferring resistance to antibiotics [51]. The ability of bacteria to form biofilm is associated with pathogenesis of numerous diseases. Biofilm formation results in chronic, persistent infections that are difficult to eradicate with antimicrobial treatment. It is believed that biofilms occur in up to 60% of human infections [52]. UPEC can persist within the bladder tissue in underlying epithelial cells or create biofilm-like pods in the recurrent cystitis [53]. Biofilm of *E. coli* may form on the urothelium and is involved in infections associated with biomaterials such as catheters or prostheses. UPEC strains are frequently isolated from biofilms formed in the lumen of catheters and showing resistance to antibiotic treatment [54]. Catheter-associated urinary tract infection (CAUTI) is the most common nosocomial infection, and approximately 80% of UTIs acquired in the hospital are associated with catheterization [55]. The insertion of indwelling catheter into the bladder increases the susceptibility of patients to UTIs, because these devices are the initiation site of infection by introducing opportunistic organisms into the urinary tract [56]. UPEC strains are capable of colonizing the intestinal and vaginal tracts, and these sites are potential reservoirs of microorganisms for UTIs and CAUTIs [57]. The urinary catheter connects the colonized perineum with the sterile bladder providing a route for bacterial entry along the catheter lumen or the external surface of the catheter [58]. CAUTI is related to the susceptibility of catheter material to microbial colonization. The initial stage of biofilm formation on a urinary catheter includes deposition of conditioning film of host urinary components, such as proteins, electrolytes, and other organic molecules [59]. These molecules on the surface of the urinary catheter may change its surface and neutralize any antiadhesive properties [60]. Planktonic bacteria are attached to the surface of the urinary catheter through hydrophobic and electrostatic interaction [61]. Development of biofilm on surface of the catheter occurs through the division of binding bacterial cells, appending additional planktonic bacteria and secretion of extracellular matrix. Detachment of single cell or group of bacterial cells from the biofilm may result in the passage of pathogens into the urine [51]. For this reason, biofilm formation on the urinary catheters is critical for initiating and maintaining of CAUTIs and is a reservoir of resistant pathogenic bacteria [62]. Several factors contribute to the formation of biofilm by *E. coli*, e.g. fimbriae, curli, and flagella. Type 1 fimbriae involved in biofilm formation may also support the colonization of urinary catheter surface [15]. The risk of CAUTI depends on the duration of catheterization, the quality of catheter care, and host susceptibility. Prolonged catheterization is the most important risk factor associated with CAUTI [62]. Long-term urinary catheter use (more than 30 days) causes permanent bacterial colonization of the urine in 100% cases [63]. Examination of people in a nursing home showed that long-term catheterization was significantly related with bacteriuria, pyelonephritis, and renal inflammation [58]. Forming of biofilm on the urinary catheters is a public health problem for patients who need these medical devices. It is recommended that patients who are chronically catheterized were treated with 5–10 days of targeted antibiotic therapy [64].

The extended spectrum of β-lactamases (ESBLs) produced by *Enterobacteriaceae* is responsible for resistance of amino and ureido penicillin, oxyimino cephalosporin, and monobactams, but not to 7-α-substituted β-lactam [74]. The production of ESBLs by UPEC strains complicates treatment because these strains are resistant not only to β-lactam antibiotics but often are also resistant to other classes of antibiotics-like aminoglycosides, quinolones, and cotrimoxazole, such as gentamicin, ciprofloxacin, and trimethoprim-sulfamethoxazole, respectively [75–77]. This reduces the treatment options to a limited number of antibiotics and empirical therapy with cephalosporins and fluoroquinolones often fail in patients with UTI [78]. Hoban et al. [79] found that these resistant microorganisms are more susceptible to the carbapenems, imipenem, and ertapenem, than to other antibiotics. ESBL-producing microorganisms were primarily considered multiresistant organisms originating in hospitals, but in recent years, the number of ESBL producers increased also among outpatients, especially related with UTIs. The authors reported 21 and 21.4% ESBL-producing *E. coli* found in community-acquired UTIs in Turkey [80] and in North India [81], respectively, while in Mexico, 31% of uropathogenic *E. coli* isolated from hospitalized patients [77] and 17.6% *E. coli* from hospitalized European UTI patients [79] were producers of ESBLs. UTIs complicated by ESBL producers tend to lead to uncertain outcomes and prolong hospitalization, especially that these organisms tend to be multidrug resistant [74]. Among ESBLs, the CTX-M enzymes are the most prevalent among isolates of UPE from inpatients and outpatients leading to serious problems for the antimicrobial management of these infections [82, 83]. There is a need for new therapy of UTI caused by

Virulence Factors and Innovative Strategies for the Treatment and Control of Uropathogenic *Escherichia coli*

http://dx.doi.org/10.5772/67778

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Currently, the antibiotic therapy is an important part of the therapeutic strategy for UTI. The increased antibiotic resistance in recent years suggests that the choice of antibiotic should be guided by the results of sensitivity assay, although in cases of community-acquired UTI, an empirical therapy is often used [23]. The drugs of first-line choice for empirical treatment of uncomplicated UTI in all European countries are fosfomycin trometamol, pivmecillinam, or nitrofurantoin macrocrystals [84]. Trimethoprim-sulfamethoxazole is also used in countries where resistance to this chemotherapeutic is low. Higher rates of side effects in comparison with other drugs limit the use of quinolones as second-line therapy. Moreover, in many countries in Europe, high resistance rates of *E. coli* strains to nalidixic acid were observed [85], and thus aminoglycosides and carbapenem are the drugs of choice. In patients with recurrent infections of the urinary tract, the antibiotics may be recommended prophylactically. It is believed that two recurrences of UTI within 6 months after therapy or three episodes per year could be considered an indication to establish prophylaxis after treatment. The drugs for this purpose are nitrofurantoin, trimethoprin-sulfamethoxazole, fosfomycin trometamol, and cotrimoxazole at lower doses than therapeutic [86]. However, repeated antibiotic treatment of UTI and prophylactic use of antibiotics frequently results in a rise in resistance to antibiotics and adversely affects microbiota of patients which may lead to secondary infections posttreatment, such as gastrointestinal infection and vaginal

multiresistant ESBL-producing UPEC.

yeast infection [87, 88].

**5. Treatment and control of UPEC**
