**11. Phylogenetic group and VF distribution among patient groups and clinical syndromes**

*E. coli* is commonly classified into four main phylogenetic groups namely A, B1, B2, and D [116] as defined by multilocus enzyme electrophoresis and multilocus sequence typing [117]. Several studies have shown that *E. coli* pathogenic strains from extraintestinal infections mostly derive from group B2, and to a less extent group D [21, 118, 119]. Most studies quote prevalence rates around 63–65% for group B2 in pathogenic strains, and 10–15% for group D [21]. Commensal *E. coli* are mainly associated with phylogenetic groups A or B1, and are mainly devoid of virulence determinants [118, 120, 121]. The overlapping associations of VFs and phylogeny with clinical virulence makes it difficult to understand which directly determines virulence. However, some studies in children showed that pyelonephritis isolates more often belonged to group B2, contained on average higher prevalences of individual VF genes, and consequently had higher VF scores than did cystitis or fecal isolates, suggesting that both VF repertoire and phylogenetic background play important roles in UTI pathogenesis.

(e.g., the aerobactin operon and afa/drab). Plasmid-borne VFs have an obvious vehicle for horizontal transmission among *E. coli* lineages. Such VFs tend to be distributed more broadly but more sporadically within the species than are chromosomal VFs [129]. Studies have demonstrated that certain VFs commonly occur together, in a way that suggests co-selection or direct genetic linkage [130, 131]. Direct genetic linkage of VFs has been shown on PAIs and

The Pathogenesis of *Escherichia Coli* Urinary Tract Infection

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Managing UTI caused by UPEC has become challenging over the years due to increasing resistance to the commonly used antibiotics [135–139], which poses a great threat to future capacity to treat UTI caused by UPEC. Although TMP-SMX has traditionally been used as a first-line treatment for UTI [140], there are reports of increased resistance to this antibiotic, which in some countries is in the range 15–20% [137]. Many UPEC strains resistant to TMP-SMZ are also resistant to amoxicillin and cephalexin. Nitrofurantoin remains highly effective against UPEC, but is mainly used for cystitis treatment due to its inability to attain sufficient serum levels to treat invasive or systemic infections [137], and all have excellent bioavailability and achieve high urinary concentrations. However, increased FQ use has resulted in a rise in the prevalence of resistance, and FQ-resistant *E. coli* has become a major problem in several countries [141].

**13. Antimicrobial drugs and uropathogenic** *Escherichia coli*

**14. Relationship between antibiotic resistance and virulence or** 

Previous studies show that in *E. coli* isolates from patients with urosepsis, resistance to antimicrobial agents such as ampicillin, sulfonamides, tetracycline, chloramphenicol, and streptomycin is negatively associated with virulence and a phylogenetic group B2, but positively associated with host compromise (immune deficiency, diabetes, and other urinary anatomical abnormalities) [26]. There is a similar negative association between FQ resistance and VFs and group B2 [142–144]. This suggests that, resistance may provide a greater fitness advantage to *E. coli* than traditional VFs or a group B2 background, allowing them to cause infections in compromised hosts with weakened defenses who are frequently exposed to antibiotics.

Determining the clonal types of UPEC is crucial for understanding the role of clonal spread to emerging antimicrobial resistance, which is important for defining and interrupting transmission pathways. Multidrug-resistant *E. coli* sequence type 131 (ST131) has emerged over the past decade as a globally disseminated cause of extraintestinal infections in humans and animals [145–147]. The recent emergence of this clone has coincided with an increase in antibiotic resistance among *E. coli* generally, suggesting a contributing role for ST131 in resistance.

**phylogenetic background in UPEC**

**15.** *E. coli* **sequence type 131 (ST131)**

plasmids [132–134].

UTI syndrome-specific differences among *E. coli* clinical and fecal isolates from men are consistent with findings from women, which have shown a gradient of virulence from *E. coli* strains causing more invasive UTI syndromes, such as pyelonephritis and febrile UTI, through those causing cystitis, to fecal strains [9, 122]. However, men are less likely than women or girls, to develop cystitis due to low-virulence strains, which is consistent with a previous observation that isolates from men with febrile UTI appeared relatively virulent, even in the presence of host compromise [122].

In most patient groups, pyelonephritis isolates tend to exhibit the highest prevalences of many individual VFs, have the highest VF scores, and are the most likely to belong to phylogenetic group B2, ST131, and a UTI-associated O type. The reported higher prevalence of pap operon genes (encoding P fimbriae) in pyelonephritis than cystitis isolates correlates with increased tropism for the kidney of P fimbriated strains [121, 123]. papGII has been shown, experimentally, to contribute to pathogenesis of pyelonephritis [124, 125], and OmpT is strongly associated with febrile UTI in men [122, 126]. However, it is not clear whether these VFs act individually or in concert with other known or unknown VFs in causing pyelonephritis.

In men and women, although cystitis and pyelonephritis isolates differ in inferred molecular virulence, phylogenetic group distribution is similar between the two clinical syndromes. However, within each phylogenetic group, VF scores exhibit a gradient across source groups (fecal < cystitis < pyelonephritis), suggesting the presence of different virulence strata within each phylogenetic group, with more virulent strains selectively causing pyelonephritis and less virulent strains being associated with cystitis and fecal isolates in that order. This suggests that VF repertoire is as, or more, important than phylogenetic background for predicting pathogenic behavior in UPEC [122, 127].

Although cystitis and pyelonephritis isolates differ significantly in inferred virulence in various patient groups, no single VF profile is unique to any clinical syndrome or patient group, implying that UTI pathogenesis is multiply determined, as suggested by several previous studies [122, 128]. Thus, intervention strategies based on VF genes might have to involve multiple targets, which would offer the extra advantage of protection against a wide range of UTI syndromes.
