Laсtiale Uro in the prevention of postmenopausal urinary infection: LACMUS study results

. Background. The purpose was to assess the efficacy and safety of Lactiale Uro, a product containing two strains of Lactobacilli plus cranberry extract and vitamin A, in preventing recurrent urinary tract infections (UTIs) in postmenopausal women (LACMUS study). Materials and methods . This was a randomized, prospective, multicenter study. Subjects received Lactiale Uro twice daily for 26 weeks after recovery from UTI; the control group didn’t receive the product. The primary endpoint was the proportion of subjects with recurrent UTI episodes at the end of the study. Results. Seventy-seven women were screened; 65 were enrolled; 61 completed the study. After 26 weeks, a significantly lower number of women experienced recurrent UTIs with Lactiale Uro compared to no treatment (9.7 vs 23.3 %; P < 0.05). Lactiale Uro produced statistically significant improvements, such as lower rates of UTI episodes (12.9 vs 36.6 %; P < 0.05); longer time to first UTI episode (136 vs 27 days; P = 0.0038); shorter duration of active UTI episode (5 vs 11 days; P = 0.0199); and shorter duration of antibacterial therapy for an active UTI episode (4 vs 10 days; P = 0.0462). Conclusions. Lactiale Uro was safe and effective for the prevention of recurrent UTIs in postmenopausal women. These data require further well-designed trials to clarify possible benefits.


Introduction
Treatment of recurrent urinary tract infections (UTIs) is an urgent problem. Three most important causes of recurrences in females: anatomical and functional disorders, sexu ally transmitted infections and postmenopause associated with a number of changes that cause a decrease in resistance to intestinal pathogens [1].
Current guidelines offer a variety of approaches to reduce UTI recurrences, including the use of natural herbal components. However, their use has no certain evidence base. For example, cranberries are considered effective when containing minimum 36 mg of proanthocyanidin (PAC) A (level of evidence: 1b, grade of recommendation: C) [2]; a lower dose is not effective. This was one of the reasons for the exclusion of cranberry products from the guidelines of the European Association of Urology (EAU) in 2014 [3].
However, combined cranberry-containing products are still popular due to their safety and quite convincing efficacy. Our attention was drawn to a study conducted by P. Koradia et al. in premenopausal women with recurrent UTIs, which results were presented in 2019 [4]. This study demonstrated the effectiveness of Bio-Kult Pro-Cyan in the prevention of recurrent UTIs in premenopausal women.
A similar product, Lactiale Uro produced by JSC Farmak, is available on the Ukrainian market. Each capsule contains a concentrate of lactic acid-producing bacteria containing Lactobacillus acidophilus, Lactobacillus plantarum 5.0 × 10 8 colony-forming units; cranberry extract containing 18 mg of PAC 254 mg; vitamin A 160 μg. We designed a study "LAСtiale uro in the prevention of postMenopaUSal urinary infection" -LACMUS. The study is an independent test of the efficacy and safety of the product similar to Bio-Kult Pro-Cyan, based on the study conducted by P. Koradia

Materials and methods
An open-label, prospective, randomized, multicenter, comparative study, LACMUS, was conducted in 61 patients (mean age 56.1 ± 1.5 years): 31 women were in the Lactiale Uro group and 30 in the control group not receiving Lactiale Uro.
The study design was completely reproduced from the original study by P. Koradia et al. [4], which became a prototype, with the only amendment -all patients were documented postmenopausal. The mean time after the last menstruation was 3.2 ± 1.5 years. In addition, the studied product Lactiale Uro had a different composition, compared to BKPro-Cyan, and contained vitamin A.
The primary endpoint was the proportion of subjects with recurrent UTI episodes at the end of the study.
Inclusion criteria: non-pregnant menopausal women aged 49 to 65 years who have experienced > 2 episodes of uncomplicated acute cystitis within the last 6 months, or > 3 episodes of uncomplicated acute cystitis within the last 12 months. Each subject enrolled in the study had to be available for the duration of the study, follow the final protocol and avoid using any supplements/products containing cranberries or probiotic supplements during the specified followup period. Each person had to have a negative pregnancy test at screening.
Exclusion criteria: active UTI; use of any antibiotic for 2 weeks after screening; known allergy to any ingredient in the study product; use of any natural product within a month prior to the study; positive pregnancy test; presence of the menstrual cycle; concomitant use of corticosteroids, anticoagulants, antidepressants, other mood-stabilizing drugs, or any medications that may interact with the supplement; significant comorbidities or conditions, including psychiatric, cardiac (including poorly controlled hypertension), renal (including anatomical disorders, catheterization, kidney stones, or kidney transplantation); hepatic (including hepatitis B or C), neurological, endocrine, metabolic (including diabetes) or lymphatic diseases, which, according to the investigator, may adversely affect the subject's participation in the study; immunodeficiency disorders (including human immunodeficiency virus); and active participation in any clinical trial within one month after the beginning of the study.
Drug administration: immediately after recovery from UTI, the next day after the last dose of an uroantiseptic (antibiotic), Lactiale Uro, 1 capsule twice daily with meals, was prescribed as a prophylactic treatment according to the instructions for use. Prescription was based on the manufacturer's instructions, which specified the period of administration as 14-21 days or as prescribed by a doctor.
The duration of the study was 6 months, 26 weeks of active follow-up of the patients. For the first month of treatment, JSC Farmak provided free Lactiale Uro as an encouraging step. The patients did not receive any fees for the inclusion or participation in the LACMUS study.
The efficacy of Lactiale Uro was assessed based on the number of patients from the group who did not develop recurrent UTIs, which was determined according to the criteria of the EAU, 2019 [5]. Lactiale Uro was not discontinued in cases of UTI exacerbation.
Each patient gave an informed consent for treatment. The local ethics committee did not evaluated the study because it did not use a pharmacological agent, as Lactiale Uro is a dietary supplement. However, each doctor who prescribed the product confirmed the possibility of its long-term use, provided a monitoring of women according to the study protocol.
At the end of the study, each patient answered 3 questions about quality of life, including: -comfort regarding urogenital system; -satisfaction with the absence of UTI recurrence; -general impression on the efficacy of UTI treatment. The evaluation was performed using a 10-point score.
Statistical processing was carried out using Chi-Square Test Calculator [6]. However, for a better comparison with the prototype, we used the same approach, i.e. descriptive statistics was used to compare findings in the two treatment groups, and these included counts and percentages for categorical data. Continuous data were summarized using mean, standard deviation (SD), median, and range (minimum and maximum values) [4].

Results and discussion
At the end of the study, 31 subjects and 30 patients from the control group were included in the analysis (Table 1).
According to  Statistical analysis comparing the efficacy of treatment is shown in Table 2.
According to Table 2, the use of Lactiale Uro resulted in a significant reduction in the number of both UTI episodes and women who experienced them. The number of recurrent episodes decreased almost fourfold (3.66). This effect was quite expected, as the amount of cranberry active substance complied with the evidence-based recommendations of the European Association of Urology (2013). Further cancellation of the recommendations regarding cranberries, in our opinion, is based on incorrect prescriptions and disregarded risk factors for the process exacerbation.
Apart from cranberries, there are many approaches in the reduction of UTI recurrences, in particular, development of autovaccines [7] or officinal preparations [8]. These measures are aimed at pathogen eradication through the body immune defense. However, adding active ingredients to cranberries can help the immune system to form local re-actions. This is exactly what we observed in the analysis of recurrence characteristics in the LACMUS study. Table 3 shows the number of UTI episodes, time to their occurrence, duration and the need for antimicrobial therapy. The presented data have significant differences, which indicate the efficacy of the used approach to Lactiale Uro administration. A very important parameter was the presence of bacteriuria at the end of the study, it was observed in 2 patients from the study group and 7 patients from the control group (X 2 (2, n = 61) = 2.074, p = 0.16776).
However, our data showed the results not as impressive as those of the selected prototype [4]. When we started the study, we expected a higher percentage of women to be able to maintain a recurrence-free course. Possible explanations may be the excessive number of risk factors in postmenopausal patients compared to premenopausal ones and possible non-compliance of the individuals with the treatment schedule for Lactiale Uro during 5 months of self-administration of the product at their own expense.
At the same time, the use of Lactiale Uro as a biological supplement showed very promising results: an almost Оригінальні статті / Original Articles twofold reduction in the number of women with recurrent UTIs during supplement administration was impressive. Discontinuations of treatment due to side effects of the product and quality of life assessments regarding urogenital complaints were also important. The mean score of satisfaction regarding the urogenital system was 7 out of 10 in those taking Lactiale Uro and 4 out of 10 in those who were not prescribed this therapy. Presumably, a long-term use of Lactobacilli, contained in the product, and vitamin A helped maintain a healthy microflora of the vagina. Administration of herbal products can significantly improve the course of UTI, sometimes competing with antibiotic therapy [9]. Such studies have recently become more active, which is associated with an increase in antibiotic re-sistance [10]. However, it should be noted that at least 3 factors contribute to recurrences in postmenopausal women: estrogen depression, changes in the anatomy of the urinary tract, and decreased sexual activity [11,12].
The LACMUS study, in our opinion, has become a litmus test that demonstrates the capabilities of a dietary product in achieving medical goals. Excellent tolerability of Lactiale Uro, an almost 4-fold reduction in the number of UTI episodes and improvement of the quality of life in postmenopausal women demonstrate the right choice in the search for optimal health status in women over 49 years. However, further research may provide additional data on the efficacy and feasibility of a long-term use of the product.

Parameter
Lactiale Uro P-value No product  , is available on the world market for the prevention of recurrent uncomplicated UTIs in premenopausal women. However, various products with similar compositions, based on the presented and prototype studies, are expected to be effective in pre-and menopausal women.

Summary of UTI episodes at the end of 26 weeks of treatment
Limitations of the study: small number of patients, lack of placebo control.

Conclusions
1. Lactiale Uro in the LACMUS study showed a significant reduction in the number of recurrent UTI episodes in postmenopausal women compared to those who did not receive it. Lactiale Uro was very well tolerated during a 6-month course; there were no discontinuations of the product.
2. Lactiale Uro showed a significant reduction in urogenital complaints in women with recurrent UTIs, which is probably due to the comprehensive action of the product.
3. The above findings allow us to consider Latiale Uro as an effective agent for the prevention of recurrent UTIs in postmenopausal women, administered as 1 capsule twice daily for at least 6 months.

Conflicts of interests.
Authors declare the absence of any conflicts of interests and their own financial interest that might be construed to influence the results or interpretation of their manuscript. JSC Farmak sponsored the first month of Lactiale Uro administration, as well as summary and presentation of the materials of the investigator-initiated study.