**4. Antimicrobial resistance of UPEC**

Antimicrobial resistance in UPEC is a clinical problem in patients with UTIs, in particular in women with recurrent UTI. The empirical antimicrobial treatment in case of recurrent UTIs exerts significant resistance pressure on the uropathogens and the fecal flora, which serves as resistance reservoirs for potential uropathogens [65–67]. Antimicrobial resistance among *E. coli* causing UTI is increasing in many countries around the world and shows considerable variations during different time periods and in different areas [68, 69].

The level of resistance of UPEC strains from hospitalized patients in Poland and Turkey to ampicillin was 56% [70, 71], while above 85% of UPEC strains from patients in India were resistant to this antibiotic [68]. High percentage (67.3%) of *E. coli* strains resistant to tetracycline was isolated from people with UTI from different parts of India [68].

Sanchez et al. [72] suggested that the increase of resistance of UPEC to ciprofloxacin is a result of widespread use of this antibiotic in the treatment of uncomplicated UTIs in the early 2000s. The most recent published data suggested that the level of resistance to trimethoprim-sulfamethoxazole increased and in different countries was over 21–24.2% [71–73]. This trend has continued for decades and the increasing resistance of *E. coli* to trimethoprim-sulfamethoxazole can be explained by frequent use of this antimicrobial agent because it is recommended as the second-line drug in treating acute uncomplicated cystitis in women. Authors reported low resistance of *E. coli* to nitrofurantoin (0.85–1.6%) and no increase in resistance in the last decade was observed [71, 72].

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 multiresistant ESBL-producing UPEC.
