Urinaty Tract Infections

Prevalence of urinary tract infections

Urinary tract infections (UTI) are among the most common bacterial infections and affect 150 million people each year all over the world. In 2007 only in the USA the physician visits due to symptoms of URI were approximately 10.5 million, and 2-3 million people visited an emergency room for a UTI. The public costs for these infections, including costs for healthcare and absences from work, are as much as approximately 3.5 billion US dollars per year only in the USA (Flores-Mireles 2015).
Failure to timely treat UTIs leads to serious consequences, including frequent relapses, pyelonephritis with sepsis, kidney injuries in young children, premature birth and complications caused by the common use of antimicrobials, for example high rate of antibiotic resistance (Flores-Mireles 2015).

Causes for UTI and risk factors

In general UTIs are classified as uncomplicated and complicated infections (Flores-Mireles 2015).
Uncomplicated UTIs affect healthy individuals with no structural or neurological abnormalities of the urinary tract. Depending on the location, these infections are divided into lower urinary tract infections (cystitis, urethritis, etc.), and infections of the upper urinary tract (e.g. pyelonephritis) (Flores-Mireles 2015).
Usually the microorganisms reach the urinary tract by ascending the urethra, particularly the microorganisms originating from the large intestine. Most often this is Escherichia coli (E. coli). This explains the higher incidence of these infections in women, as well as the increased risk of infection after catheterization or other intervention on the urinary bladder (Sabitha 2016). E. coli is responsible for up to 75% of UTIs. Other 20-25% of UTIs are mostly caused by Staphylococcus saprophyticus (6%), Кlebsiella spp. (6%), Enterococcus spp. (5%), Group B streptococcus (3%), P.mirabilis(2%), Candida spp. (1%) (Flores-Mireles 2015).
Uncomplicated urinary infections in women are predominantly caused by E.coli, which migrates from the perianal region to the vaginal entrance and urethra. The following increase the risk for development of such infections (Hooton 1996):
  • Sexual activity 
  • Use of contraceptive devices and spermicides
  • Genetic predisposition to urinary infections

Mechanisms for infection onset. Bacterial strains virulence.

Not all microorganisms cause urinary tract infections equally easy. The urinary tract is relatively inhospitable for bacterial colonization. On order to colonize, pathogens must resist the frequent exfoliation of the epithelium, as well as the washing effect of the evacuating urine. For this reason the most important factor for urinary tract colonization is the ability of the uropathogens to adhere to the urothelium (Sabitha 2016). Over 80% of the uropathogenic bacteria are capable to attach to the urothelial cells (Gunther 2001).
Most bacteria species, causing UTIs, are equipped with special virulent factors – organelles called fimbriae or pili, supporting the bacterial attachment and ascending (Sabitha Baby 2016).
As mentioned above, the most recognized etiologic pathogen of both uncomplicated and complicated UTIs are the uropathogenic E.coli (Flores-Mireles 2015). They possess capabilities, called virulent factors, which are not seen in the non-pathogenic strains. Е.coli  cause UTI mainly by binding via fimbriae with specific receptors on the surface of the urinary tract. The most important virulent factors, which E. coli express, are the fimbriae (Sabitha Baby 2016).
Fimbriae are small thin fibers appended to the surface of the bacterial cells, which are responsible for their adhesion to the epithelium layer (Pokhrel 2016).

eshericia coli

Fimbriae are divided into two main groups – type 1 fimbriae and type P fimbriae. Type 1 fimbriae mediate bacterial adhesion to a mannose-containing receptor widely spread on the epithelial cells surface in urinary tract.  They are most common fimbriae expressed by pathogenic E.coli (Sabitha Baby 2016).

eshericia coli
eshericia coli

Type P fimbriae are the second most common virulence factor of uropathogenic E.coli. They consist of heteropolymeric fibres composed of different protein subunits, encoded by the pap A-K gene operon (Kucheria 2005). These fimbriae recognize kidney glycosphingolipids carrying the Gal a(1–4)Gal determinant via its papG adhesin. They are important in the pathogenesis of ascending UTI and pyelonephritis in humans and have been identified in 80% of pyelonephritic E coli isolates (Plos 1995). P fimbriae are the second most important factor for adhesion of pathogenic bacteria to urinary tract epithelial cells. Type P fimbriae are expressed by majority of E. coli strains, causing acute pyelonephritis (90%) and by several strains responsible for asymptomatic bacteriuria (Sabitha Baby 2016).
As a result of the binding of both fimbriae types to the uroepithelial cells, uropathogens adhere to the epithelium, multiply, colonize and form a steady biofilm. The regulated expression of type 1 and type P fimbriae allows the bacteria to move through the urinary tract and to reach the kidneys via the ureters. (Emődy 2003) Type 1 fimbriae are the most common virulent factor, expressed by E. coli. They determine the bacterial virulence in the urinary bladder infections. It has been established that almost all E.coli strains, which cause acute cystitis, express type 1 fimbriae (Lim 1998). Thus, E. coli are the most recognized (in as much as 95%) cause of uncomplicated UTI in women (Wiles 2008).
The most common uncomplicated UTI in women is the acute cystitis (Concia 2017). Acute cystitis often presents with urinary symptoms which include dysuria, urinary frequency urgency, suprapubic pain or tenderness, and occasionally hematuria (Li 2018).
Uncomplicated cystitis is associated with recent sexual intercourse, use of spermicides, past asymptomatic bacteriuria, relapsing UTIs, infant or advanced age at the first UTI occurrence, UTI of the mother. Other risk factors are vaginal infection, diabetes, obesity, genetic predisposition and others (Flores-Mireles 2015).
Due to the anatomical and physiological changes in the kidneys and the urinary tract during pregnancy, the urinary current may be slowed weakened the bladder may not evacuate completely. This is one of the reasons for the increased incidence of UTI during pregnancy. Majority of symptomatic UTI during pregnancy manifest with acute cystitis (Delzell, 2000).

Treatment

There is no single medication considered as the most appropriate for the treatment of cute uncomplicated cystitis, according to the guidelines of 2010, and the choice among the recommended pharmacologic agents should be individualized. The choice of antibiotic depends on its efficacy, risks for side effects, the level of resistance and the ability to cause concurrent impairment (i.e. unfavorable effects of the antibiotic therapy which may allow the proliferation of resistance organisms and colonization or infection with multi-resistant organisms). In average, patients start to note improvement in symptoms within 36 hours of initiation of treatment (Kucheria 2005).

Trimethoprim-sulfamethoxazole. A 3-day course of trimethoprim-sulfamethoxazole (TMP-SMX) leads to elimination of the pathogens within 7 days after initiation of treatment in approximately 94% of treated women (Warren 1999). A single-dose treatment is less effective than a 3-day course, with percent of elimination reaching 87%, however the single dose is associated with less adverse reactions (11% versus 18%) (Warren 1999). TMP-SMX is recommended in regions where the prevalence of drug-resistance E. coli strains, causing cystitis, is less than 20%. (Warren 1999; Kucheria 2005).

Nitrofurantoin. Although fewer than 5% of isolates from urine are resistant to nitrofurantoin, it is significantly less effective as compared to TMP-SMX against aerobe Gram-negative bacteria, different from E. coli. It is commonly well tolerated, but is often prescribed for seven days which may lead to serious gastrointestinal disorders. Macrocrystaline nitrofurantoin is administered at 6 hours intervals, and the monohydrate – twice daily. Monohydrate formulation is associated with fewer side effects. Nitrofurantoin is not linked to plasmid-mediated resistance and is an appropriate choice for patients with recent exposure to other antimicrobials. (Fihn 2003; Kucheria 2005).

Fluoroquinolones offer excellent activity and are usually well tolerated. (Henry 2002) Fluoroquinolone resistance is as rare as 5% in most regions. (Hooton 2004; Warren 1999) It is being reported that prevalence of resistant isolates increases all over the world (although not that rapidly for TMP-SMX) (Yamamoto 2010; Muratani and Matsumoto 2006). A study in Japan reported fluoroquinolone resistance in approximately 8% of isolates from patients with uncomplicated cystitis. (Yamamoto 2009). The increasing resistance to ciprofloxacin of E. coli strains isolated in acute uncomplicated cystitis is disturbing – from 15.2% in 2002 to 23.4% in 2006 in South Korea (Yamamoto 2010; Kucheria 2005).

Ofloxacin is more efficacious than TMP-SMX (Hooton 1991).

Other fluoroquinolones have similar efficacy, however they need to be considered as second-line treatment in order to maintain the sensitivity of uropathogens to this group of antibiotics. Their use in uncomplicated cystitis should be limited to patients who are allergic to cheaper drugs, those with history of exposure to antimicrobials causing bacterial resistance, and regions where the resistance to TMP-SMX is greater than 20% (Kucheria 2005). When TMP-SMX is contraindicated, a 3-day course of ciprofloxacin, levofloxacin, norfloxacin, lomefloxacin or gatifloxacin is an appropriate alternative.  It is important to note that fluoroquinolones are less effective against S. Saprophyticus and a number of Gram-negative uropathogens. (Fihn 2003; Kucheria 2005).

Fosfomycin tromethamine is administered as a single dose in the form of powder and is another treatment option in uncomplicated cystitis. It is less effective than TMP-SMX and fluoroquinolones and should be prescribed only when more effective agents cannot be used. (Warren et al., 1999). An additional limitation of fosfomycin tromethamine is its poor efficacy against S. Saprophyticus (Kucheria 2005).

D-mannose is a sugar monomer, which is naturally found in wood and in the fruit of numerous plants. As compared to other sugar monomers, it most frequently takes part in cellular processes.  Its role in prevention of parasitic, bacterial, viral and fungal infections has been established. Apart from that D-mannose supports the immune system since it is necessary for the production of special substances, called cytokines (Toyota 1989; Ofek 1982). The role of D-mannose in inhibiting the adhesion of E. coli to the uroepithelium has been extensively studied. In the beginning of bacterial invasion, E. coli attach to the epithelium of the urinary bladder via mannose-sensitive fimbriae type 1. After the adhesion of the pathogens to the uroepithelium, they start to form microcolonies and bacterial biofilm.

After oral administration of D-mannose, its plasma levels increase, it reaches the kidneys unchanged and is then filtered into urine.  Uropathogenic E. coli with mannose-sensitive fimbriae type 1 form steady complexes with the D-mannose in urine. D-mannose bound fimbriae cannot attach to the uroepithelium and the pathogen is then excreted with urine. It has also been proven that D-mannose decreases the adhesion strength of pathogens which are already attached to the uroepithelium. Diminished adhesion strength facilitates the removal of the pathogens with forced diuresis, as well as the secondary binding of fimbriae type 1 to D-mannose, forming stronger complexes. D-mannose exhibits marked anti-inflammatory activity, by stimulating mannose receptors on macrophages (Toyota 1989; Ofek 1982).

Cranberry. The standardized extract from cranberry fruit (Vaccinum macrocarpon) contains numerous biologically active ingredients, the most significant for the UTI treatment being the type A proanthocyanidins (PACs), which are a class of flavonoids, named earlier as tannins (Plos 1995). These compounds block the second most frequent factors of bacterial virulence – E. coli fimbriae type P. Similarly to D-mannose, type A proanthocyanidins decrease the adhesion potential of pathogens (Hisano 2012). Morphological changes in uropathogenic E. coli under the impact of type A proanthocyanidins were also established – elongation of the bacterial cells, shortening and loss of fimbriae (Hisano; 2012). Inhibiting the adhesion to the uroepithelium and decreasing the adhesion potential in already attached pathogens leads, on one hand, to inhibition of microcolonies formation, and, on the other, allows for removal of the pathogen with urine (González de Llano 2015). Type A proanthocyanidins (PACs), play a significant role in inhibition of the biofilm formation by the uropathogens, by blocking the production and secretion of indole by the E. coli. Indole is a signaling molecule, secreted by bacteria, which facilitates the formation of the biofilm (Pinzón-Arango 2008).

Birch leaves extract. The standardized birch leaves extract (Betula pendula) possesses rich chemical composition. The extract contains various biologically active agents, which directly influence the treatment of UTI and of acute cystitis, in particular. They belong to different chemical groups: flavonoids, betulinic acid, tannins, dammarane triterpenes, and potassium nitrate (EMA/HMPC/573240/2014).

a) Flavonoids are the most characteristic class of chemical compounds in higher plants, identified mainly as pigments. Flavonoids are synthesized in plants in response to microbial infection, and have proven in vitro antimicrobial activity against a broad spectrum of microorganisms (Akiyama 1987).
Flavonoids have an established antibacterial and urinary antiseptic activity – through inhibition of receptors (tyrosinekinase) in bacterial cells, responsible for important cell processes (Akiyama 1987).
Flavonoids hyperoside and quercetin exhibit anti-inflammatory activity by suppressing degranulation of mastocytes thus inhibiting the release of histamine (Middleton 1985).
Quercetin suppresses the release of leukotrienes and other prostaglandin precursors, which are essential elements of the inflammatory process (Davis 2011). It has a marked spasmolytic effect on the urogenital system (EMEA/HMPC/285759/2007).  White birch leaves are one of the most abundant sources of quercetin (Costea 2015).   
Hyperoside in the composition of birch leaves extract possesses a distinct diuretic effect. Potassium nitrate in the standardized extract intensifies the diuretic activity of flavonoids (Akiyama 1987).
The diuretic activity of the birch leaves extract is mild and allows for long-term use without compromising the water-electrolyte balance (Raudonė L1 2014).

b) Terpenes are included in the composition of plants etheric oil. Standardized birch leaves extract contains dammarane type tetracyclic terpenes (2014 EMA/HMPC/573240/2014).
Tetracyclic triterpenes have lipophilic structure, which serves for the destruction of the cell membrane of various bacterial species. This property of triterpenes is responsible for their antibacterial activity. Tetracyclic triterpenes are also moderate spasmolytics (Zengin 2014).

c) Tannins are a group of phenolic compounds in the composition of the birch leaves extract. They exhibit antibacterial activity by forming strong hydrogen bonds with specific receptors on the cell wall surface of microorganisms. Tannins possess anti-inflammatory activity, too, expressed by stimulation of phagocytosis and cell mediated immunity. The astringent effect of tannins on the tissues along the urinary tract is well known (Haslam 1996).

d) The diuretic effect of biologically active agents (mainly flavonoids) contributes for the elimination of L-foassesrms (bacteria with impaired integrity or complete loss of cell wall). L-forms are predominantly responsible for chronic and recurring UTI (Errington  2016). Forced diuresis changes the osmolality of urine to hypotonic, i.e. to lower osmotic pressure.  Under the pressure of the established osmotic gradient, water from urine influxes into the L-form (protoplast). This leads to destruction of the protoplast and its elimination from the organism with the forced diuresis (Errington 2016).

Arctostaphylos uva-ursi (uva-ursi or bearberry). It is reported bearberry to have diuretic, urinary antiseptic, astringent and anti-inflammatory properties (EMA. Assessment report on Arctostaphylos uva-ursi 2012). The extract constituents include flavonoids, iridoids, hydroquinone glycosides (mainly arbutin), tannins and terpenoids. In-vitro studies have demonstrated antibacterial activity against a variety of organisms including Escherichia coli, the most prevalent urinary pathogen. The antimicrobial action has been attributed to the hydroquinone derivatives, especially arbutin (EMA. Assessment report on Arctostaphylos uva-ursi 2012).

Hightlights

Escherichia coli is the most frequent causе for cystitis (Howell 2010).

The choice of antimicrobial therapy for the treatment of acute uncomplicated cystitis depends on probability of a multi-resistant Gram-negative agent causing the infection (Howell 2010).

Parallel to initiating the treatment, it is recommended to evaluate urine culture and antibiotic susceptibility. This is particularly important in patients who have risk factors for antimicrobial resistance (Howell 2010).

First line antibacterial therapy
In patients with acute uncomplicated cystitis and no risk factors for multi-resistant Gram-negative infection, the preferred agents for empiric first line antibacterial therapy are nitrofurantoin monohydrate, trimethoprim-sulfamethoxazole, fosfomycin (Howell 2010).

Alternative antibacterial therapy
If there are factors which impact the use of the above mentioned antimicrobials, like allergies or suspected bacterial resistance, the beta-lactam antibiotics are appropriate oral medications. If the patient has contraindications for the use of beta-lactam antibiotics, fluoroquinolones are a reasonable choice. However, they should be spared for more serious infections (Howell 2010).

High risk for resistance
In patients with risk factors for multi-drug resistant (MDR) Gram-negative infection, a sample for urine culture and bacterial susceptibility should be obtained before initiation of treatment (Howell 2010).

In patients with symptoms persisting for more than 48 to 72 hours after initiation of empiric antimicrobial therapy, and those with recurrent symptoms within several weeks of beginning of treatment, urine culture and uropathogen susceptibility should be evaluated. If symptoms remain steady despite administration of adequate antimicrobial therapy, an X-ray should be considered for evaluation for anatomical anomalies (Howell 2010).

Biologically active agents
The pharmacological advantages of the biologically active agents in the composition of the standardized extracts of birch leaves and cranberry, as well as D-mannose for the treatment of acute uncomplicated cystitis, are summarized below:

  • D-mannose binds to E. coli fimbriae type 1, thus interfering with adhesion to the uroepithelium.
  • Type A proanthocyanidins in the cranberry extract bind to the fimbriae type P, inhibit the attachment to the epithelium and the advancement of E.coli along the urogenital system. 
  • The concurrent administration of D-mannose and A proanthocyanidins decreases the adhesion strength of already attached pathogens, by blocking over 95% of the fimbriae of the uropathogenic bacteria, thus facilitating their removal with urine.
  • Inhibition of adhesion, weakening the attachment, blocking the secretion of indole as a result of the effect of the flavonoids in the above mentioned extracts, stops the formation of microcolonies and biofilm of pathogens, which suppresses the development of infection.
  • Flavonoids, tetracyclic triterpenes and tannins in the birch leaves and cranberry extracts exert antibacterial and urinary antiseptic activity.
  • Flavonoids, tannins and D-mannose possess a marked anti-inflammatory activity.
  • Flavonoids and potassium nitrate in the birch extract have a pronounced diuretic effect, which is mild and allows for long-term use without compromising the water-electrolyte balance.
  • The spasmolytic and astringent activity of tannins and tetracyclic triterpenes alleviate cystitis symptoms of pain and burning sensation when urinating by reducing mucosal swelling.
  • The diuretic effect of flavonoids reduces the probability of chronic course of infection and the recurrence rate, by eliminating the L-forms of the uropathogens. 


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