AppCiroximately 15% ofca il 15% degli antibiotics ari viene prescribed for the treatment of urinary tract infections (UTIs), which are some of the most common bacterial infections. UTIs affect overtto per il trattamento delle infezioni del tratto urinario (UTI), che sono alcune delle infezioni batteriche più comuni. Le infezioni delle vie urinarie colpiscono oltre 400 million people annually and result inioni di persone ogni anno e provocano 150 million deaths worldwideioni di decessi in tutto il mondo [ 1 , 2 ^[1][2]]. It Sis estimated that around 50% of women and 5% of men will experience a UTI during their lifetime stima che circa il 50% delle donne e il 5% degli uomini sperimenteranno una IVU nel corso della loro vita [ 3 ^[3]]. The L’incidence of UTIs increases with age, affecting between 30% and 50% of women over the age of 60za delle infezioni del tratto urinario aumenta con l’età, colpendo tra il 30% e il 50% delle donne di età superiore ai 60 anni [ 4 ^[4]]. UTILa pathogenesis is the result of several complex delle infezioni delle vie urinarie è il risultato di numerose interactions between a uropathogen and the hostzioni complesse tra un uropatogeno e l'ospite [ 5 , 6 ^[5][6]]. HoweTuttaver, it is widely recognised that outpatientia, è ampiamente riconosciuto che l’uso ambulatoriale di antibiotic use is often exi è spesso eccessive and unno e non necessaryio [ 7 ^[7]]. Sebbene Whilegli antibiotics have been used to treat common infections for many years,i siano stati usati per trattare le infezioni comuni per molti anni, la resistenza agli antibiotic resistance has made severali ha reso inefficaci diversi antibiotics that are commonly used for UTIs ineffective, leading to more serious illness, hospital admissions, and deathsi comunemente usati per le infezioni del tratto urinario, portando a malattie più gravi, ricoveri ospedalieri e decessi, nonché ad un aumento dei costi sanitari [ 6 , 8 as] well as increased healthcare costs ^[6][8]. A. La resistenza agli antibiotici è resistance is a major concern, withuna delle principali preoccupazioni e le infezioni delle vie urinarie resistenti agli antibiotic-resistant UTIs being ai rappresentano un aspetto critico [ 9 ]. Lal aspectresistenza ^[9].agli Aantibiotic resistance wasi è stata identified by the World Health cata dall’Organization as one of the top tenzzazione Mondiale della Sanità come una delle dieci principali minacce global public health threats in 2021i alla salute pubblica nel 2021 [ ^[10]10 ]. A urUn'infezinary tract infection that spreads to the bloodstream and causesone del tratto urinario che si diffonde nel flusso sanguigno e causa sepsis can b può essere fatal, and drug-resistant infections can make this more likelye e le infezioni resistenti ai farmaci possono renderlo più probabile [ 6 , 11 ^[6][11]]. InNel 2019, drug-resistant infections directly caused 1.27 million of the approximately 4.95 million deaths le infezioni resistenti ai farmaci hanno causato direttamente 1,27 milioni dei circa 4,95 milioni di decessi attributed toiti alla resistenza agli antibiotic resistance. This exceeded the number of deaths caused by i. Ciò ha superato il numero di decessi causati dall’HIV/AIDS [ 12 ^[12][13], 13 ]. AntibioticLa resistance is a natural phenza agli antibiotici è un fenomenon, but its naturale, ma la sua acceleration due to the misuse ofzione dovuta all’abuso di antibiotics in humans andi nell’uomo e negli animals is a serious i costituisce un problema ^[14]serio [ 14 ]. ThCis is especially concerning for UTIs, which are among the most prevalent infectious diseasesò è particolarmente preoccupante per le infezioni del tratto urinario, che sono tra le malattie infettive più diffuse [ 15 ^[15]]. BI biofilms are widely recognised as a major sono ampiamente riconosciuti come uno dei principali fattori che contributing factor of the high rates of recurrence andiscono agli alti tassi di recidiva e resistenza agli antibiotic resistance that are commonly associatedi comunemente associati alle infezioni del tratto urinario [ 16 with, UTIs17 ^[16][17]]. BI biofilms can b possono essere formed by different types of bacteria, including both ati da diversi tipi di batteri, comprese le specie Gram-positive ande Gram-negative species, and they are known to play an , ed è noto che svolgono un ruolo important role in several diseasee in diversi processesi patologici [ 18 , 19 ^[18][19]]. 

2.  Classification and Pathzione e patogenesis of delle IVUTIs

2.1. Types of UTIs

2.1. Tipi di infezioni del tratto urinario

There are several classification systems for UTIs [20]. However, the most widely used systems are those developed by the CDC, which distinguish between uncomplicated and complicated UTIs on the basis of the presence of risk factors such as anatomical or functional abnormalities in the urinary tract ^[5][6][21][5,6,21]. UTIs are also classified according to the location of the infection and the clinical presentation of the UTI [6]. The urinary tract consists of the kidneys, ureters, bladder, and urethra. The kidneys filter waste products from the blood and produce urine, which then passes through the ureters to the bladder. UTIs are typically categorized as upper or lower depending on their location within the urinary tract. Urethritis is an inflammation of the urethra, and ureteritis is an inflammation of the ureter [22]. Lower UTIs, including cystitis, which refers to a bladder infection, and upper UTIs, such as pyelonephritis involving the kidney, are classified based on the affected area [23]. In healthy, pre-menopausal, non-pregnant women with no history of an abnormal urinary tract, acute cystitis and pyelonephritis are the classifications for uncomplicated UTIs, with women being more commonly affected than men [24]. Complicated UTIs involve functional or metabolic abnormalities, such as obstruction, urolithiasis, pregnancy, diabetes, neurogenic bladder, renal, or other immunocompromising conditions [25]. Recurrence, catheter association, and urosepsis are also included in the classification of UTIs [26]. UTIs are classified as recurrent if two or more episodes occur within six months or three or more episodes occur within 12 months ^[27][28][27,28]. Catheter-associated urinary tract infections (CAUTIs) account for around 75% of all hospital-acquired UTIs [29]. The risk of contracting these infections increases with prolonged use of a urinary catheter, which is a tube inserted into the bladder through the urethra to drain urine. Urosepsis is a systemic inflammatory response to UTIs such as cystitis, bladder infection, and pyelonephritis, and it can lead to multiple organ dysfunction, failure, and even death [30].

2.2. Clinical Syndromes

Diagnosing UTIs can be challenging, especially in patients with non-specific symptoms [31]. However, it is crucial to differentiate between UTIs and asymptomatic bacteriuria to determine the necessity of antibiotic treatment [6]. Asymptomatic bacteriuria is the presence of one or more bacterial species in urine, as indicated by a positive urine culture, in a patient who does not exhibit any signs or symptoms of a UTI (see below) [32]. In contrast, UTIs are infections that can affect the urethra, bladder, ureters, and/or kidneys. The symptoms experienced depend on which part of the urinary tract is affected ^[4][32][4,32]. Table 1 shows the signs and symptoms of UTIs depending on the location of the bacterial infection. UTIs are more common in women and typically affect the bladder and urethra [18]. Uropathogens commonly infect the urinary tract through an ascending route that starts in the genital area, passes through the urethra to the bladder, and then ascends the ureters to reach the kidneys (Figure 1). Cystitis is a prevalent UTI among women, especially pregnant women, due to pregnancy’s interference with bladder emptying [33]. Women are more susceptible to cystitis due to the shorter length of their urethra and its proximity to the anus. Recurrent episodes of cystitis are common among women, especially during their reproductive years, as bacteria can travel from the urethra to the bladder during sexual intercourse [34]. Bladder infections in women can also be caused by the use of a diaphragm for contraception or the decrease in estrogen production after menopause [35]. The spermicide used in conjunction with a diaphragm suppresses the natural vaginal flora, allowing the bacteria responsible for cystitis to thrive [21]. Bladder prolapse can occur as a result of decreased estrogen production during menopause, which can make it difficult to empty the bladder and increase the risk of bladder infections [36]. In men, cystitis and urethritis are frequently caused by bacterial prostatitis resulting from ascending urethral infection or intraprostatic reflux [37]. If antibiotics fail to eliminate all bacteria, such as when they do not penetrate the prostate adequately or when treatment is discontinued prematurely, prostatitis may recur and become chronic [38]. Bacteria that persist in the prostate gland have a tendency to re-infect the bladder. Cystitis can also result from a urethral stone obstructing urine flow, preventing the removal of residual bacteria that can rapidly multiply in the bladder, or from a catheter that introduces bacteria into the bladder [4]. Urethritis is an infection of the urethra, which is the tube that carries urine from the bladder to the outside of the body. Symptoms of urethritis typically include pain during urination, a strong urge to urinate, and sometimes discharge (which is more common in men than women) [39]. The most common causes of urethritis are sexually transmitted microorganisms, such as Neisseria, Chlamydia, Herpes simplex virus, and Trichomonas [40]. Pyelonephritis is a type of urinary tract infection (UTI) that typically originates in another part of the urinary tract, such as the urethra or bladder, and then spreads to one or both kidneys [41]. In rare cases (about 5%), infections can also spread to the kidneys from other parts of the body through the bloodstream [4]. Pyelonephritis is more common in women than in men and may be milder and more difficult to recognize in children and the elderly [41]. Risk factors of pyelonephritis include kidney stones, catheterization, urinary anatomical abnormalities, reflux, diabetes mellitus, enlarged prostate, and pregnancy [6].

2.3. Urinary Tract Infections Caused by Bacteria

UTIs are caused by both Gram-negative and Gram-positive bacteria [42]. Uropathogenic Escherichia coli is the most common pathogen found in both uncomplicated and complicated UTIs. This bacterium is responsible for at least 80% and 65% of community- and hospital-acquired UTIs, respectively [6]. For several decades, it was believed that the bladder and urethra of healthy individuals were sterile or contained too few bacteria to cause infections [43]. However, recent studies have shown evidence of numerous microorganisms in the bladder of adult humans without clinical infections. The relevance and contribution of these microorganisms to health and disease are still under investigation ^[43][44][43,44]. Common pathogens causing UTIs include Enterococcus faecalis, Proteus mirabilis, Klebsiella pneumoniae, Staphylococcus saprophyticus, Group B Streptococcus, Pseudomonas aeruginosa, and S. aureus [6]. Uropathogens express fimbrial adhesins that bind to glycolipids and glycoproteins on the mucosal–epithelial surface of the host (Figure 2) [45]. Adhesins are used by uropathogens to create biofilms on both biotic and abiotic surfaces, enabling them to colonise the mucosa of the urinary tract and indwelling devices such as urinary catheters [46]. Furthermore, some pathogens secrete substances, such as hemolysin, capsule, proteases, and phospholipases, which aid bacterial invasion by disrupting epithelial integrity ^{[45][47][48][49][50]}[45,47,48,49,50]. Additionally, certain uropathogens, such as UPEC, can invade the host’s epithelial cells and replicate within them, creating a reservoir for recurrent infections [51]. This enables the bacteria to colonise and cause UTIs. Bacterial virulence factors, such as fimbriae, adhesins, P and type 1 pili, and others that facilitate bacterial invasion, have been described in detail in previous comprehensive reviews (Figure 2) ^{[4][6][45][52]}[4,6,45,52].