Urinary tract infection (UTI) is among the most common community-acquired infections, and it has a very high rate of recurrence. Of women diagnosed with UTI, 35% to 53% have a recurrence within 12 months. The standard treatment for UTI is a course of antibiotics; however, there is not a standard prophylactic treatment for recurrent UTI. Now that the relationship is understood between overuse of antibiotics and the development of multidrug-resistant strains within microbial populations, the authors argue that it is imperative to develop a long-term standard preventive therapy for recurrent UTI.
In this prospective, non-randomized phase II clinical trial, researchers at the Department of Urology at the Santa Chiara Regional Hospital in Trento, Italy evaluated a combination of natural therapy for recurrent UTI. The product is produced by Anatek Health Italia, Milan, Italy, and is sold under the name AVIUR Retard. Each tablet contains the following combination of proprietary products: 200 mg of Ellirose, a sambubioside-containing extract of hibiscus (Hibiscus sabdariffa, Malvaceae) flower [Note: Information on extraction solvent, dry extract ratio (DER), and quantitative information on Sambubioside content is not disclosed.]; 100 mg of Protexil, a protease obtained from fermentation of maltodextrin by koji (Aspergillus oryzae, Trichocomaceae) fungus; 100 mg of Serrazimes, a proteolytic enzyme blend obtained from the Serratia species E-15 bacteria; and 60 mg of Myrliq, an extract of myrrh (Commiphora myrrha, Burseraceae) standardized for curzerene, furanoeudesma-1,3-diene, and lindestrene [Note: Information on extraction solvent, DER, and information on the “standardized content” of the specified constituents is not disclosed.]. Outcome measures for the study were the number of symptomatic UTIs and quality of life (QoL) score.
All women who came into the clinic with recurrent UTI between September and December 2017 (n=55) consented to be enrolled in the study. At baseline, the patients completed a QoL questionnaire, and researchers collected and cultured a mid-stream urine sample. All patients were treated with antibiotics and confirmed to be infection-free. The last isolated bacterial strain from each patient was recorded and considered in the final analysis.
All patients in the study were treated with AVIUR Retard. For the first seven days of treatment, patients were to take one tablet each morning and each evening. From then on, they were instructed to take one tablet only in the evening for 10 days, and to repeat the 10-day, one-tablet dose cycle each month. Patients received phone calls to ensure compliance. After three months and again after six months, the patients had follow-up urological appointments at which they again completed QoL questionnaires and a midstream urine sample was cultured. In case of recurrence of acute symptomatic UTI, the patients received a course of antibiotics, in accordance with the European Association of Urology (EAU) guidelines. For this study, a microbial colony count greater than 105 units/mL was considered an infection.
In order to generate relevant clinical information, the researchers included all women who presented at the hospital with recurrent UTI. Exclusion factors were limited to overactive bladder, anatomical abnormalities, previous surgery of the urinary tract, complicated UTI, pregnancy, urinary catheterization, and an active sexually transmitted disease.
The primary outcome measure was the rate of recurrence of UTI during the study period. A good response to treatment was defined as less than two UTIs in six months. Treatment failure was defined as no reduction in recurrence rate. The transition from active UTI to asymptomatic bacteriuria (ABU) was not considered treatment failure.
Fifty-five women were enrolled in the study, with an average age of 49.3 years, ranging from 28 to 61 years. The most common pathogen identified in the initial urine samples was Escherichia coli, which occurred in 63.7% of the samples. All patients had sterile urine following antibiotic treatment. The median number of UTIs per six months was five.
At three months into the study, there was a significant improvement in QoL score. Forty-three of 51 patients (84.3%) reported QoL improvement (P<0.001). Forty-two of 51 (82.3%) reported: “restore to a pre-UTI situation.” The urine culture tests showed that 78.4% continued to have sterile urine, while 11 (20%) had transitioned from E. coli to Enterococcus faecalis, that is, from UTI to ABU. Adherence to the therapy was very high. One patient discontinued the tablets due to nausea.
Inappropriate use of antibiotics has led to an increase in multidrug-resistant strains of pathogenic microbes. This is a global health challenge that demands action. This study is part of a movement toward better antibiotic stewardship. The EAU currently has no standard protocol for prophylactic management of recurrent UTI. This phase II trial demonstrates the efficacy and safety of AVIUR Retard for this use; however, future trials should address the limitations of this present study including larger cohort size and lack of randomization. Compliance was optimal despite a somewhat complicated treatment schedule. This suggests that the population with recurrent UTI is highly motivated.
The researchers report significant improvements (P<0.001) in every outcome variable
measured, i.e., number of UTIs, QoL score, and bacterial counts. Of particular interest is the transition from UTI to ABU. While approximately 60% of the patients had sterile urine at the end of the study, 40% had transitioned from microbes that cause UTI symptoms to microbes that cause ABU. ABU may protect against the establishment of symptomatic UTI causing microbial populations. This study establishes AVIUR Retard does not interfere with normal commensal flora. In this regard, its use may be preferable to repeated courses of antibiotics.
AVIUR Retard may reduce the host response to nonpathogenic microbial activity. Its components have complementary and overlapping anti-inflammatory effects. Ellirose may reduce the levels of several inflammation markers induced by endotoxin. Protexil can initiate a cascade that reduces cytokine activity. Serrazimes may have a similar action to Protexil and may potentially block the release of pain-signaling compounds. Myrliq can inhibit the formation of many classes of inflammatory compounds.
The authors recommend AVIUR Retard for motivated recurrent UTI patients, emphasizing that its use offers the additional community health benefit of reducing antibiotic use. They acknowledge that their study was small and not randomized, and advocate for further trials on AVIUR Retard for recurrent UTI.
The authors declare no conflict of interest.
Cai T, Tiscione D, Cocci A, et al. Hibiscus extract, vegetable proteases, and Commiphora myrrha are useful to prevent symptomatic UTI episode in patients affected by recurrent uncomplicated urinary tract infections. Arch Ital Urol Androl. September 2018;90(3):203-207. doi:10.4081/aiua.2018.3.203.