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2BACTERIAL CYSTITIS
1Sarkisova Victoria Vladimirovna, 2Yusupova Dildora Uktamovna, 3Shernazarov Farrukh,
4Hasibur Rehman
1,2Lecturer of Samarkand State Medical University 3,4Student of Samarkand State Medical University https://doi.org/10.5281/zenodo.10213604
Abstract. Every year, the development of bacterial cystitis is the reason for seeking medical help for 7 million women around the world.
Keywords: microbiome, gardnerella vaginalis.
Such a high prevalence of pathology among the fair sex is not accidental and is associated with a number of risk factors, which include sexual intercourse, the presence of inflammatory diseases of the vulva and vagina, incompetence of the pelvic floor muscles, atrophic vaginitis caused by estrogen deficiency during menopause [ 6]. Gynecologists often encounter the presented reasons for the possible development of an inflammatory process in the bladder in their practice and must take measures aimed at preventing the development of bacterial cystitis. Despite the apparent simplicity of diagnosis and treatment of bladder inflammation, the selection of adequate therapy is associated with a whole complex of difficult problems. Firstly, for a long time, experts have noted an increase in antibiotic resistance of leading microorganisms that provoke the occurrence of urinary tract infections (UTIs), and secondly, treatment of the latter in women often leads to disruption of the microbiome of the vulva and vagina, which leads to an increased risk of re-infection of the lower parts of the urinary system [7]. Previously, researchers had already established the identity of the microflora of the vagina and urethra in 80% of cases [8]. This confirmed the fact that the ascending route of infection in women is dominant. It is known that the location of the external opening of the urethra near the reservoirs of uropathogens - the anus and vagina - predisposes to infection of the periurethral area. Then there is a sequential migration of microorganisms into the bladder, where they can be colonized or eliminated, depending on the result of the host-pathogen interaction. There is no doubt that the development of such a mechanism is facilitated by the weakening of the primary protective barrier. The effectiveness of the latter is ensured by lactobacilli, which normally make up 96-98% of the total microbiome in healthy women, both from the vagina and from the distal urethra. The described microorganisms in the mucous membrane adhere tightly to epithelial cells, forming a biofilm consisting of microcolonies of lactobacilli surrounded by the products of their metabolism - the glycocalyx. Unfortunately, the hormonal changes that women undergo throughout their lives, namely puberty, menstruation, pregnancy, menopause, can have a negative impact on the quantitative characteristics of the microbiome. Violation of its constant composition not only leads to a weakening of the protective barrier, but also increases the possibility of adhesion and reproduction of opportunistic microorganisms [10-14]. It is important to note that a number of antibacterial drugs used for the treatment of cystitis can also have a negative effect on the quantitative composition of lactobacilli. This entails the formation of vaginal dysbiosis, manifested in the form of bacterial vaginosis (BV) or even vaginitis, which can provoke frequent exacerbations and a protracted course of the inflammatory process in the urogenital tract. To overcome such a vicious circle, it is advisable to use medications that do not disrupt the normal biocenosis of the genital
mucosa. The use of drugs that do not lead to the development of vaginal dysbiosis during UTI treatment is also supported by the fact that Gardnerella vaginalis can act as a trigger for exacerbation of chronic cystitis in women. Before describing this mechanism, we note that the most common cause of the disease remains enterobacteria, mainly Escherichia coli (80%). The latter is a representative of the normal intestinal microflora, but its uropathogenic strains are capable of adhesion to the urothelium and can interfere with the development of the immune response. In addition, this type of microorganism is capable of tissue invasion into the bladder mucosa. This feature makes the pathogen resistant to antimicrobial therapy and allows it to form dormant intracellular bacterial reservoirs. The urinary tract is regularly exposed to vaginal bacteria, including Gardnerella vaginalis. Moreover, as studies have shown, even a short stay of Gardnerella vaginalis in the bladder can provoke reactivation of latent E. coli cells [15, 16]. Understanding this possible development of the clinical situation should not only be a reason for timely detection and treatment of vaginal infections by a gynecologist, but also requires a differentiated approach to the selection of therapy for patients with a history of recurrent cystitis. The anatomical and physiological features of the structure of the female urinary and reproductive systems, the presence of risk factors for possible reinfection, as well as the continuous increase in antibiotic resistance of microorganisms significantly complicate the selection of adequate and effective therapy for patients. In order to find ways to solve this problem, a prospective multicenter microbiological study DARMIS was conducted in 2018. Its implementation made it possible to once again confirm that the main causative agent of uncomplicated urinary tract infection remains E. coli, reaching 74.6% of observations. With the development of a complicated urinary tract infection, this microorganism was isolated in 67.2% of cases. The remaining bacteria leading to the development of uncomplicated and complicated forms of the infectious disease were Klebsiella pneumoniae in 9.6% and 12.7% of observations, P. mirabilis - in 3% and 4.6% of observations, Enterococcus faecalis - in 5% and 6% of cases. ,3% of observations, Staphylococcus spp. - in 2.3% and 1.2% of observations.
Every year, the development of bacterial cystitis is the reason for seeking medical help for 7 million women around the world. On the territory of the Russian Federation, the occurrence of this disease is recorded in 15-20 thousand per 1 million people per year, while in 10% inflammation of the bladder takes on a recurrent form [1-5]. Such a high prevalence of pathology among the fair sex is not accidental and is associated with a number of risk factors, which include sexual intercourse, the presence of inflammatory diseases of the vulva and vagina, incompetence of the pelvic floor muscles, atrophic vaginitis caused by estrogen deficiency during menopause (Table) [ 6]. Gynecologists often encounter the presented reasons for the possible development of an inflammatory process in the bladder in their practice and must take measures aimed at preventing the development of bacterial cystitis. Despite the apparent simplicity of diagnosis and treatment of bladder inflammation, the selection of adequate therapy is associated with a whole complex of difficult problems. Firstly, for a long time, experts have noted an increase in antibiotic resistance of leading microorganisms that provoke the occurrence of urinary tract infections (UTIs), and secondly, treatment of the latter in women often leads to disruption of the microbiome of the vulva and vagina, which leads to an increased risk of re-infection of the lower parts of the urinary system [7]. Previously, researchers had already established the identity of the microflora of the vagina and urethra in 80% of cases [8].
This confirmed the fact that the ascending route of infection in women is dominant. It is known that the location of the external opening of the urethra near the reservoirs of uropathogens
- the anus and vagina - predisposes to infection of the periurethral area. Then there is a sequential migration of microorganisms into the bladder, where they can be colonized or eliminated, depending on the result of the host-pathogen interaction [9]. There is no doubt that the development of such a mechanism is facilitated by the weakening of the primary protective barrier. The effectiveness of the latter is ensured by lactobacilli, which normally make up 96-98% of the total microbiome in healthy women, both from the vagina and from the distal urethra. The described microorganisms in the mucous membrane adhere tightly to epithelial cells, forming a biofilm consisting of microcolonies of lactobacilli surrounded by the products of their metabolism
- the glycocalyx. Unfortunately, the hormonal changes that women undergo throughout their lives, namely puberty, menstruation, pregnancy, menopause, can have a negative impact on the quantitative characteristics of the microbiome. Violation of its constant composition not only leads to a weakening of the protective barrier, but also increases the possibility of adhesion and reproduction of opportunistic microorganisms [10-14]. It is important to note that a number of antibacterial drugs used for the treatment of cystitis can also have a negative effect on the quantitative composition of lactobacilli.
This entails the formation of vaginal dysbiosis, manifested in the form of bacterial vaginosis (BV) or even vaginitis, which can provoke frequent exacerbations and a protracted course of the inflammatory process in the urogenital tract. To overcome such a vicious circle, it is advisable to use medications that do not disrupt the normal biocenosis of the genital mucosa. The use of drugs that do not lead to the development of vaginal dysbiosis during UTI treatment is also supported by the fact that Gardnerella vaginalis can act as a trigger for exacerbation of chronic cystitis in women. Before describing this mechanism, we note that the most common cause of the disease remains enterobacteria, mainly Escherichia coli (80%). The latter is a representative of the normal intestinal microflora, but its uropathogenic strains are capable of adhesion to the urothelium and can interfere with the development of the immune response. In addition, this type of microorganism is capable of tissue invasion into the bladder mucosa. This feature makes the pathogen resistant to antimicrobial therapy and allows it to form dormant intracellular bacterial reservoirs. The urinary tract is regularly exposed to vaginal bacteria, including Gardnerella vaginalis. Moreover, as studies have shown, even a short stay of Gardnerella vaginalis in the bladder can provoke reactivation of latent E. coli cells [15, 16]. Understanding this possible development of the clinical situation should not only be a reason for timely detection and treatment of vaginal infections by a gynecologist, but also requires a differentiated approach to the selection of therapy for patients with a history of recurrent cystitis.
The anatomical and physiological features of the structure of the female urinary and reproductive systems, the presence of risk factors for possible reinfection, as well as the continuous increase in antibiotic resistance of microorganisms significantly complicate the selection of adequate and effective therapy for patients. In order to find ways to solve this problem, a prospective multicenter microbiological study DARMIS was conducted in 2018. Its implementation made it possible to once again confirm that the main causative agent of uncomplicated urinary tract infection remains E. coli, reaching 74.6% of observations. With the development of a complicated urinary tract infection, this microorganism was isolated in 67.2% of cases. The remaining bacteria leading to the development of uncomplicated and complicated
forms of the infectious disease were Klebsiella pneumoniae in 9.6% and 12.7% of observations, P. mirabilis - in 3% and 4.6% of observations, Enterococcus faecalis - in 5% and 6% of cases. ,3% of observations, Staphylococcus spp. - in 2.3% and 1.2% of observations, respectively. In addition to the frequency of isolation of various types of pathogens in patients with bacterial cystitis, the resistance of strains to antibacterial drugs was also determined. The leading pathogen of the disease, E. coli, demonstrated resistance to ampicillin in 57.7% of cases, amoxicillin/clavulanate in 43%, and trimethoprim/sulfamethoxazole in 36.9% of cases. Researchers also noted a decrease in its sensitivity to ciprofloxacin to 60.6% versus 79.9%, which was recorded in 2011 [17, 18]. Obtaining such results led to a revision of previously used treatment regimens. The range of approved drugs for the treatment of UTIs is presented in the clinical guidelines of the Ministry of Health of the Russian Federation dated 2021, "Cystitis in Women," as well as in the federal clinical guidelines of 2022, edited by the All-Russian public organization "Russian Society of Urologists."
The anatomical and physiological features of the structure of the female urinary and reproductive systems, the presence of risk factors for possible reinfection, as well as the continuous increase in antibiotic resistance of microorganisms significantly complicate the selection of adequate and effective therapy for patients. In order to find ways to solve this problem, a prospective multicenter microbiological study DARMIS was conducted in 2018. Its implementation made it possible to once again confirm that the main causative agent of uncomplicated urinary tract infection remains E. coli, reaching 74.6% of observations. With the development of a complicated urinary tract infection, this microorganism was isolated in 67.2% of cases. The remaining bacteria leading to the development of uncomplicated and complicated forms of the infectious disease were Klebsiella pneumoniae in 9.6% and 12.7% of observations, P. mirabilis - in 3% and 4.6% of observations, Enterococcus faecalis - in 5% and 6% of cases. ,3% of observations, Staphylococcus spp. - in 2.3% and 1.2% of observations, respectively. In addition to the frequency of isolation of various types of pathogens in patients with bacterial cystitis, the resistance of strains to antibacterial drugs was also determined. The leading pathogen of the disease, E. coli, demonstrated resistance to ampicillin in 57.7% of cases, amoxicillin/clavulanate in 43%, and trimethoprim/sulfamethoxazole in 36.9% of cases. Researchers also noted a decrease in its sensitivity to ciprofloxacin to 60.6% versus 79.9%, which was recorded in 2011 [17, 18]. Obtaining such results led to a revision of previously used treatment regimens. The range of approved drugs for the treatment of UTIs is presented in the clinical guidelines of the Ministry of Health of the Russian Federation dated 2021, "Cystitis in Women," as well as in the federal clinical guidelines of 2022, edited by the All-Russian public organization "Russian Society of Urologists." The anatomical and physiological features of the structure of the female urinary and reproductive systems, the presence of risk factors for possible reinfection, as well as the continuous increase in antibiotic resistance of microorganisms significantly complicate the selection of adequate and effective therapy for patients. In order to find ways to solve this problem, a prospective multicenter microbiological study DARMIS was conducted in 2018. Its implementation made it possible to once again confirm that the main causative agent of uncomplicated urinary tract infection remains E. coli, reaching 74.6% of observations. With the development of a complicated urinary tract infection, this microorganism was isolated in 67.2% of cases. The remaining bacteria leading to the development of uncomplicated and complicated forms of the infectious disease were Klebsiella pneumoniae in 9.6% and 12.7% of observations, P. mirabilis - in 3% and 4.6% of observations, Enterococcus faecalis - in 5% and 6% of cases. ,3% of observations, Staphylococcus spp. - in
2.3% and 1.2% of observations, respectively. In addition to the frequency of isolation of various types of pathogens in patients with bacterial cystitis, the resistance of strains to antibacterial drugs was also determined. The leading pathogen of the disease, E. coli, demonstrated resistance to ampicillin in 57.7% of cases, amoxicillin/clavulanate in 43%, and trimethoprim/sulfamethoxazole in 36.9% of cases. Researchers also noted a decrease in its sensitivity to ciprofloxacin to 60.6% versus 79.9%, which was recorded in 2011 [17, 18]. Obtaining such results led to a revision of previously used treatment regimens. Nifuratel is also interesting because it has a spectrum of activity not only against the main uropathogens, but also against the causative agents of certain vaginal infections, and is also suitable for the treatment of acute and chronic lower urinary tract infections. The effectiveness of nifuratel in the treatment of acute cystitis in women can be confirmed by data from a prospective observational study of the effectiveness of antimicrobial therapy for acute uncomplicated cystitis with nifuratel (MacMirror) in 35 women (regimen - 400 mg 3 times a day orally for 7 days). The comparison group (35 patients) received nitrofurantoin 100 mg 2 times a day orally for 7 days. Evaluation of efficacy and safety indicators was carried out on the 3rd and 7th days of administration. As a result, after 3 days of therapy in the group of patients taking nifuratel, the disappearance of imperative urges was observed in 94.2% of cases, the disappearance of leukocytes in the urine - in 82.8% of people. After 7 days of treatment with nifuratel, complete resolution of symptoms was achieved in all patients, leukocyturia was relieved in 97.1%. In the group taking nitrofurantoin, after three days, imperative urges disappeared in 83.8% of women, leukocyturia was stopped in 77.4% of people. After 7 days, the urgency also disappeared in all patients, but leukocyturia only in 90.4% of women. In the first group of patients, adverse reactions were noted in only 8.5% of people, in the second - in 41.9%. A similar study was carried out in 2018 and included 65 women with uncomplicated cystitis. All patients included in the study were prescribed nifuratel at a dosage of 200 mg 3 times a day. The course of therapy was 7 days. In such a short period, clinical effectiveness was achieved in 97% of observations, bacteriological - in 94%. A control examination 30 days after the end of treatment demonstrated not only the absence of complaints, but also absolutely normal values of the results of clinical and laboratory examination in 64 patients. Based on the data obtained, the authors absolutely correctly and justifiably came to the conclusion that nifuratel is not only effective in the treatment of cystitis, but also its use allows you to quickly relieve the symptoms of the disease, the manifestation of which makes it difficult for patients to live their usual lifestyle [24]. In addition to the pronounced positive effect obtained in patients with uncomplicated cystitis, the undeniable advantage of nifuratel lies in the possibility of its use as monotherapy in the presence of combined infection of the bladder and vagina. A prospective observational study conducted by E. V. Kulchavenya involved 23 women with exacerbation of chronic cystitis and concomitant BV [25]. Note that among those observed, in addition to BV, 19 (82.6%) patients were also diagnosed with vulvovaginal candidiasis. All subjects were prescribed nifuratel in tablets of 200 mg 3 times a day for 7 days. The effectiveness of therapy was monitored 7, 90 and 180 days after completion of the course of therapy. At the end of therapy, 73.9% of patients showed complete resolution of the symptoms of cystitis and BV, 17.4% had a significant improvement, only 2 patients (8.7%) considered the change in their condition insignificant. After 3 months of observation, in 81.8% of cases there were no disturbances in urination and discharge from the genital tract, moderate dysbiosis in the form of Candida spp. was determined only in 3 (13.6%) cases. Within six months after completion of monotherapy with nifuratel, the patients had no complaints, and bacteriuria
was not detected. In all women, normal vaginal coenosis was restored with a sufficient amount of Lactobacillus spp. Achieving absolute normalization of urine tests and vaginal microbiota, as well as the cessation of bacteriuria, allowed the author to confirm the bidirectional effect of nifuratel [25]. The study proved its high effectiveness in relation to both nosologies. The presented results of studies assessing the effectiveness of nifuratel and carried out during 2000-2020 suggest that it has high activity against the main causative agents of acute urogenital infections, including not only the main uropathogens (E. coli, Enterococcus spp., Klebsiella spp. ., Staphylococcus aureus, Enterococcus spp., etc.), but also causative agents of vaginal infections (causative agents of BV, including Atopobium vaginae, fungi of the genus Candida albicans, Trichomonas vaginalis) [26]. The undeniable advantage of nifuratel is the absence of its activity against Lactobacillus spp., which makes it possible to normalize the microflora of adjacent reservoirs of infection, vagina and intestines, thereby preventing relapses of cystitis [27]. An important aspect is the possibility of using nifuratel in pregnant women based on a benefit/risk assessment.
Obviously, the treatment of acute and recurrent forms of cystitis is not the task of gynecologists. However, timely identification and selection of drugs to eliminate vulvovaginal infections are the direct responsibility of these specialists and lead to a reduction in the risk of developing bladder inflammation. For this purpose, in case of recurrent cystitis, it is advisable to recommend nifuratel in the form of vaginal dosage forms, in combination with nystatin (for example, Macmiror complex, capsules, cream). This treatment regimen will not only completely eliminate the pathogenic microorganism from the mucous membrane of the vulva and vagina, but will also not require a second stage of treatment aimed at restoring the microbiome of the genital tract. As a result, the doctor will be able to significantly reduce the duration of therapy, providing a personalized approach to the patient, which in turn will lead to improved quality of medical care at the outpatient stage.
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