Non-antibiotic versus antibiotic prophylaxis for recurrent urinary tract infections (NAPRUTI)
Samenvatting van de aanvraag
Urinary tract infections (UTI) are very common infections in women. For women with UTIs which recur more than two times per year low dose antibiotic prophylaxis for several months is indicated. However, this can lead to resistance of not only the causative microorganisms, but also of the commensal flora. The increasing prevalence of Escherichia coli isolates (the most prevalent uropathogen) that are resistant to antimicrobial agents has stimulated interest in novel non-antibiotic methods for the prevention of UTIs. Studies have demonstrated that prophylaxis with non-antibiotic compounds may lead to a lower incidence of UTI recurrence rates compared to placebo. The combination of two orally administered Lactobacillus strains (Lactobacillus rhamnosus GR-1 and L. fermentum RC-14) reduces vaginal colonization by potential pathogenic bacteria. Furthermore, the reappearance of vaginal lactobacilli in postmenopausal women, brought about by estrogen therapy, is associated with a lower incidence of UTIs. In addition to colonization, adherence of uropathogens to the bladder mucosa is another essential step in the pathogenesis of UTIs. Cranberries contain fructose and proanthocyanidine, which inhibit the adherence of type 1 fimbriae of E. coli (the most important virulence factor in cystitis) and the expression of P fimbriae (the most important virulence factor in pyelonephritis), respectively. Ingestion of cranberry juice leads compared to placebo to a lower incidence of bacteriuria and symptomatic UTIs in women. The question arises how these forms of non-antibiotic prophylaxis compare to antibiotic prophylaxis. (Near) equal effectiveness would be attractive given their potential to considerably lower the prevalence of microbial resistance to antibiotics. In two interlinked randomized clinical equivalence trials, we aim to investigate the effect of a 12-months non-antibiotic prophylaxis on the development of antibiotic resistance. The trials will be carried out in women who have an indication for prophylaxis of recurrent UTIs. Both trials first set out to show nearly equal effectiveness in terms of UTI recurrence rates. Standardized antibiotic prophylaxis will consist of 12 months of trimethoprim-sulfamethoxazole (TMP-SMX) or ciprofloxacin (in the case of TMP-SMX allergy or resistance at baseline). In trial A, 280 pre-menopausal women will receive either cranberries or standardized antibiotic treatment. In trial B, 280 postmenopausal women will receive either lactobacilli capsules or standardized antibiotic treatment. Since pre-menopausal women have normal vaginal lactobacilli concentrations it makes no sense to supplement them with lactobacilli capsules. Both trials assume a 95% effectiveness rate of antibiotics in terms of recurrent UTIs. Equivalence is defined as a UTI effectiveness rate of the non-antibiotic treatment no less than 85%. The trial is adequately powered to detect a 15% difference in favour of cranberries and lactobacilli in terms of the development of microbial resistance. In both trials, the primary endpoints are the 12-months (cumulative) recurrence rates of symptomatic UTIs, and the time to the first occurrence of bacterial resistance in urine and faecal samples.