Phenolic acid content and antiadherence activity in the urine of patients treated with cranberry syrup (Vaccinium macrocarpon) vs. trimethoprim for recurrent urinary tract infection
Introduction
The evidence currently available supports the long-term use of antibiotics in subtherapeutic doses to control recurrent urinary tract infection (UTI) (Jepson, Williams, & Craig, 2012). However, a major problem in this respect is the resulting increase in bacterial resistance to antibiotics and the selection of multiresistant bacterial flora (Gupta, 2003). Trimethoprim, which is frequently used in the treatment of UTI, is eliminated primarily by the kidney after glomerular filtration and tubular secretion. Concentrations of trimethoprim are considerably higher in urine than in the blood. After oral administration, 50–60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolised trimethoprim. Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. This binding is much stronger for the bacterial enzyme than for the corresponding mammalian enzyme. Thus, trimethoprim selectively interferes with the bacterial biosynthesis of nucleic acids and proteins. Most studies have focused on changes occurring in vitro, leaving unresolved certain questions regarding the clinical significance in vivo. Various authors have used a murine urinary tract infection model to explore the potential impact of low-dose antibiotics on pathogenesis. It has been shown, using in vitro models, that subinhibitory antibiotics prime uropathogens for adherence and invasion (Goneau et al, 2015, Uberos et al, 2001).
Other studies have reported the usefulness of cranberry in treating recurrent UTI, in both adults and children (Beerepoot et al, 2011, Uberos et al, 2012). Cranberry extract contains at least two chemical constituents that have been associated with antiadherent properties: on the one hand, fructose inhibits the adherence of the type 1 fimbriae of some bacteria to the epithelium (Zafriri, Ofek, Adar, Pocino, & Sharon, 1989); on the other, proanthocyanidins (PACs) inhibit the adherence of P fimbriated Escherichia coli to the urothelium (Foo et al, 2000, Miyazaki et al, 2002). Studies have established that after the ingestion of cranberry, the concentrations of PACs in urine are at the limits of detectability (Iswaldi et al., 2013), although some metabolites derived from PACs, such as phenolic acids, do present varying concentrations of PACs in the urine (Fernandez-Puentes et al., 2015).
The recurrence of UTI after pyelonephritis can reach 20% (Garin et al., 2006). It has been recommended (American Academy of Pediatrics, Committee on Quality Improvement Subcommittee on Urinary Tract Infection, 1999) that all cases of UTI in children aged two months to two years, after antibiotic treatment for a period of 7–14 days, should be treated with antibiotics until imaging studies are completed. However, later evidence (Garin et al, 2006, Mathews et al, 2009) suggests that antibiotic prophylaxis does not reduce renal scarring, even in patients with high-grade reflux, and so its usefulness has been questioned.
Other studies (Craig et al, 2009) have shown that paediatric patients with recurrent UTI who are treated with trimethoprim-sulphamethoxazole at low doses experienced a 6% reduction in the risk of UTI compared with a placebo group (95% CI: 1–11).
In the present study, we consider the antiadherent properties of the urine of patients included in a clinical trial and treated with cranberry syrup vs. trimethoprim for the treatment of recurrent UTI, through an analysis of phenolic acid excretion in urine and its association with: 1) the alteration of surface hydrophobicity and, 2) with the inhibition of biofilm formation by E. coli.
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Materials and methods
The study is based on a Phase III randomised double-blind intervention, with two branches: one with cranberry extract in a 3% glucose syrup and the other with trimethoprim. Over a period of two years, children aged 1 month to 13 years, treated at the nephrology and urology departments of our hospital, were recruited to the study population. The maximum follow up of each such patient was one year. The trial was approved by the local ethics committee and in all cases written informed consent was
Effectiveness of cranberry syrup in preventing the recurrence of urinary infection
The following subjects were recruited to the study: 85 children under 1 year of age, 53 of whom were treated with trimethoprim and 32 with cranberry syrup; 107 children over 1 year of age, 64 of whom were treated with trimethoprim and 43 with cranberry syrup.
Among the children under 1 year of age, the rate of UTI associated with trimethoprim treatment was 19% (95% CI 4–35) in the boys and 43% (95% CI 18–68) in the girls. In the children under 1 year of age, the rate of UTI associated with
Discussion
Our study confirms that cranberry syrup is similar to trimethoprim treatment for recurrent UTI in children and infants, although in the latter case its effectiveness is considered inferior to that of trimethoprim at the doses used in our study. Furthermore, we find that cranberry syrup treatment at this dose is safe in infants and children.
In 1984, Sobota (1984) observed that cranberry interferes with the adhesion of P-fimbriated E. coli to the epithelium, and showed that this could be one of
Acknowledgement
This study was funded by Institute of Health Carlos III (Spain) (PI07-0274).
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2017, FitoterapiaCitation Excerpt :fruits are a suitable natural source of phenolic compounds, such as procyanidins (PACs), anthocyanins, flavones and phenolic acids and they are used as traditional remedies for the treatment of urinary tract infections (UTIs) being largely investigated for this activity [1–7]. PACs with at least 1 A-type linkage (PAC-A) represent in general the 51–91% of total cranberry PACs [7] and are considered to exert anti-adhesive activity against uropathogenic bacteria, although their mechanism of action is still under debate [1–3,8–22]. The clinical efficacy of cranberry in prevention and treatment of UTIs has attracted the interest of several researchers, however conflicting results have been obtained on is effectiveness [9,10,23–26].
5-(3′,4′-Dihydroxyphenyl)-γ-valerolactone and its sulphate conjugates, representative circulating metabolites of flavan-3-ols, exhibit anti-adhesive activity against uropathogenic Escherichia coli in bladder epithelial cells
2017, Journal of Functional FoodsCitation Excerpt :Nevertheless, the presence of monohydroxyphenyl-valeric acids (both free and sulphated) was detected only at trace levels. Cranberry consumption has been indicated to be effective in decreasing the occurrence and severity of UTI in women (Rodríguez-Mateos et al., 2014b; Uberos et al., 2015). This fact has been attributed to the ability of cranberry A-type PACs to inhibit the adherence of UPEC to the bladder epithelium (Polewski et al., 2016; Rodríguez-Mateos et al., 2014b).
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