**1. Introduction**

Urinary tract infections (UTI) are among the most common bacterial infections in humans. Approximately 50%-60% of adult women experience a UTI during their lifetime. Further‐ more, a significant number of patients can be characterized as having recurrent UTIs if they meet the criteria of ≥2 uncomplicated UTIs in 6 months or ≥3 positive cultures within the preceding 12 months. Applying this definition, it is estimated that recurrent UTIs affect 25% of women with a history of UTI.

E. coli represents the main causative pathogen in recurrent UTI and is responsible for ap‐ proximately 80% of all episodes of infection. Further important pathogens include Proteus mirabilis, Staphylococcus saprophyticus, and Klebsiella pneumonia.

Symptomatic UTIs cause significant discomfort such as dysuria, polyuria, and suprapubic tenderness. If left untreated, a UTI can progress to acute pyelonephritis with the risk of per‐ manent renal scarring and loss of renal function.

Patients with recurrent urinary tract infections undergo frequent antibiotic treatment and/or low-dose antibiotic prophylaxis. Additionally, a subset of patients is required to undergo a systematic radiological and endoscopic evaluation of the urinary tract in order to rule out any underlying structural abnormalities or urinary calculi. The immense use of antibiotics for the treatment of urinary tract infections has resulted in the development of considerable bacterial resistance and therefore, increasing difficulties in eradicating infections. Due to the development of bacterial resistance, UTIs are a substantial economic burden and a notewor‐ thy public health issue. Therefore, new treatment strategies and preventive measures against UTIs such as immune-stimulation/modulation, vaccine development, the use of pro‐

biotics, and the instillation of attenuated bacteria into the urinary bladder are currently be‐ ing researched.

et al., 2006, Ofek et al., 1991, Ohnishi et al., 2006). More recently, other compounds such as flavanoids, anthocyanins, catechin, triterpenoids, organic acids and ascorbic acid were iden‐ tified as constituents (Raz et al., 2004). A wide variety of cranberry products are employed as treatment, the most common are cranberry juice concentrate, cranberry juice cocktail, and capsules. In respect to prevention, randomised trials suggest that cranberry juice or cranber‐ ry-concentrate tablets reduce the risk of symptomatic recurrent infection by 12-20%, espe‐ cially in pre-menopausal women (Avorn et al., 1994, Kontiokari et al., 2001, Stothers, 2002). The same results do not apply to men, elderly patients, or those requiring catheterization (Jepson &Craig, 2008). When compared to the current standard of antibiotic treatment, tri‐ methoprim-sulfamethoxazole 480mg daily is more effective than cranberry capsules 500mg twice daily to prevent recurrent UTIs over 12 months (Beerepoot et al.). High withdrawal rates were common in these trials, as was the inability to confirm compliance with cranberry prophylaxis. While some randomized clinical trials could not demonstrate that cranberry is beneficial (Jepson et al., 2000), other clinical and epidemiological studies support the use of cranberry in maintaining a healthy urinary tract (Perez-Lopez et al., 2009). Another pro‐ posed mode of action is the non-enzymatic generation of nitric oxide under acidic condi‐ tions(MacMicking et al., 1997). Nitric oxide has significant anti-microbial activity. Up until now, no evidence exists that cranberry extracts are effective to treat UTIs, while some data

Immune-Based Treatment Strategies for Patients with Recurrent Urinary Tract Infections – Where Are We?

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support its use as prophylactic agent in the prevention of UTIs (Guay, 2009).

Berberine sulfate is an alkaloid found in the Berberine arisata plant, as well as the roots of Oregon Grape (Mahonia aquifolium), Goldenseal (hydrastis canadensis), and Goldenthread (Coptis chinesis). It is present in the root, rhizome, and stem bark of the plants (Yarnell, 2002). Head et al. could show that berberine extracts are effective against a variety of organ‐ isms, including bacteria, viruses, fungi, and protozoans (Head, 2008). Growth inhibitory ef‐ fects were described for several bacterial pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa,, E. coli, Bacillus subtilis and Chlamydia (Cernakova &Kostalova, 2002, Head, 2008, Scazzocchio et al., 2001). In one study berberine was found to decrease synthesis and expression of E. Coli Pap fimbriae, thus decreasing bacterial adhesion to epi‐ thelia *in vitro* (Sun et al., 1988). Similarly, berberine sulfate was found to prevent Streptococ‐ cus pyogenes to adhere to host cells (Sun et al., 1988). Another potentially important mode of action, is the alteration of the bacterial cell division through targeting the FtsZ protein (Domadia et al., 2008). However, the mechanisms behind the anti-microbial properties of berbine are not well studied. Although berberine has been included in Chinese urinary med‐ ications for centuries, no *in vivo* studies or clinical trials have been published to evaluate its

Blueberry, part of the Vaccinium genus, is closely related to cranberry. Studies suggest that high molecular weight pranthocyanidins found in wild blueberry inhibit E. Coli adhesion *in vitro* (Head, 2008, Ofek et al., 1996, Ofek et al., 1991). It was also shown, that the constituents

*3.1.1. Berberine*

effectiveness.

*3.1.2. Blueberry*

This chapter will review the most recent literature and provide up-to-date information on developments in immune-based treatment strategies for patients with recurrent UTIs from a pre-clinical and clinical point of view.
