Phenolic acid content and antiadherence activity in the urine of patients treated with cranberry syrup (Vaccinium macrocarpon) vs. trimethoprim for recurrent urinary tract infection

https://doi.org/10.1016/j.jff.2015.08.009Get rights and content

Highlights

  • Some metabolites of cranberry such as hydroxybenzoic acid or hydroxycinnamic acid, may also be responsible for the antibacterial effects described in vivo.

  • Our study confirms that the effect of cranberry and trimethoprim may be similar in the prophylaxis of recurrent urinary tract infection in children.

  • Our study confirms that the cranberry is safe and effective in the prophylaxis of urinary tract infection in child.

Abstract

The effectiveness of cranberry in the treatment of urinary tract infection (UTI) has been associated with its polyphenol content, particularly proanthocyanidins (PACs) and the inhibition of adherence of Escherichia coli to the uroepithelium. This paper describes a controlled, double blind, clinical trial of children aged over one month with recurrent urinary tract infection. The study aims were to evaluate the safety and efficacy of cranberry syrup in children and to investigate the relationship between the excretion of phenolic acids in urine with the antiadherent activity of cranberry syrup.

In the study population, cranberry syrup was found to be similar to trimethoprim, with a rate of UTI (reinfection) of 26% (95% CI 12–41). The administration of cranberry syrup was associated with high levels of hydroxycinnamic and hydroxybenzoic acids in urine; in both cases these molecules present activity in the biofilm inhibition or reduction of surface hydrophobicity of E. coli (Clinical Trials Registry ISRCTN16968287).

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.

Section snippets

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).

References (36)

  • L.Y. Rios et al.

    Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects

    American Journal of Clinical Nutrition

    (2003)
  • A.E. Sobota

    Inhibition of bacterial adherence by cranberry juice: Potential use for the treatment of urinary tract infections

    The Journal of Urology

    (1984)
  • S. Stepanovic et al.

    A modified microtiter-plate test for quantification of staphylococcal biofilm formation

    Journal of Microbiological Methods

    (2000)
  • M.A. Beerepoot et al.

    Cranberries vs antibiotics to prevent urinary tract infections: A randomized double-blind noninferiority trial in premenopausal women

    Archives of Internal Medicine

    (2011)
  • A. Borges et al.

    Antibacterial activity and mode of action of ferulic and gallic acids against pathogenic bacteria

    Microbial Drug Resistance (Larchmont, N.Y.)

    (2013)
  • L. Bravo

    Polyphenols: Chemistry, dietary sources, metabolism, and nutritional significance

    Nutrition Reviews

    (1998)
  • J.C. Craig et al.

    Antibiotic prophylaxis and recurrent urinary tract infection in children

    The New England Journal of Medicine

    (2009)
  • P. Di Martino et al.

    Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice: A double-blind randomized placebo-controlled cross-over trial

    World Journal of Urology

    (2006)
  • Cited by (8)

    • The antiadhesive activity of cranberry phytocomplex studied by metabolomics: Intestinal PAC-A metabolites but not intact PAC-A are identified as markers in active urines against uropathogenic Escherichia coli

      2017, Fitoterapia
      Citation 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 Foods
      Citation 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).

    • Cranberries for preventing urinary tract infections

      2023, Cochrane Database of Systematic Reviews
    • Cranberries for preventing urinary tract infections

      2023, Cochrane Database of Systematic Reviews
    View all citing articles on Scopus
    View full text