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Article Contents

Conclusions, supplementary data.

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Definitions of Urinary Tract Infection in Current Research: A Systematic Review

M. P. B. and R. M. H. J. contributed equally to this work.

Potential conflicts of interest. All authors: No reported conflicts.

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Manu P Bilsen, Rosa M H Jongeneel, Caroline Schneeberger, Tamara N Platteel, Cees van Nieuwkoop, Lona Mody, Jeffrey M Caterino, Suzanne E Geerlings, Bela Köves, Florian Wagenlehner, Simon P Conroy, Leo G Visser, Merel M C Lambregts, Definitions of Urinary Tract Infection in Current Research: A Systematic Review, Open Forum Infectious Diseases , Volume 10, Issue 7, July 2023, ofad332, https://doi.org/10.1093/ofid/ofad332

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Defining urinary tract infection (UTI) is complex, as numerous clinical and diagnostic parameters are involved. In this systematic review, we aimed to gain insight into how UTI is defined across current studies. We included 47 studies, published between January 2019 and May 2022, investigating therapeutic or prophylactic interventions in adult patients with UTI. Signs and symptoms, pyuria, and a positive urine culture were required in 85%, 28%, and 55% of study definitions, respectively. Five studies (11%) required all 3 categories for the diagnosis of UTI. Thresholds for significant bacteriuria varied from 10 3 to 10 5 colony-forming units/mL. None of the 12 studies including acute cystitis and 2 of 12 (17%) defining acute pyelonephritis used identical definitions. Complicated UTI was defined by both host factors and systemic involvement in 9 of 14 (64%) studies. In conclusion, UTI definitions are heterogeneous across recent studies, highlighting the need for a consensus-based, research reference standard for UTI.

Urinary tract infection (UTI) refers to a plethora of clinical phenotypes, including cystitis, pyelonephritis, prostatitis, urosepsis, and catheter-associated UTI (CA-UTI) [ 1 , 2 ]. In both clinical practice and in research, the diagnosis of UTI is based on a multitude of clinical signs and symptoms and diagnostic tests. Signs and symptoms can be further subdivided into (1) lower urinary tract symptoms, such as dysuria, frequency, and urgency; (2) systemic signs and symptoms, such as fever; and (3) nonspecific signs and symptoms, such as nausea and malaise. Commonly used diagnostic tests include urine dipstick for determining the presence of leukocyte esterase and nitrites, microscopy or flow cytometry for quantification of pyuria, and urine and blood cultures.

When defining and diagnosing UTI, numerous combinations of signs, symptoms, and outcomes of diagnostic tests are possible, and this diversity is reflected in various research guidelines. For drug development and approval purposes, the European Medicines Agency (EMA) [ 3 ] and US Food and Drug Administration (FDA) [ 4 , 5 ] have developed guidelines for clinical trials evaluating antimicrobials for the treatment of UTI, summarized in Table 1 . These guidelines provide definitions for uncomplicated UTI, complicated UTI, and acute pyelonephritis. McGeer et al [ 6 ] have developed research guidelines for studies in long-term care facilities (LTCFs). Clinical practice guidelines include the Infectious Diseases Society of America (currently being updated) [ 7 ] and European Association of Urology [ 8 ] guidelines. It is important to distinguish between research guidelines and clinical practice guidelines as the latter are meant for treatment recommendations, and the definitions in these clinical guidelines are generally based on often limited diagnostic information available when assessing a patient in the clinical, near-patient setting.

European Medicines Agency and US Food and Drug Administration Definitions of Uncomplicated and Complicated Urinary Tract Infection

In the EMA guidelines, bacteriuria definitions were mentioned in the description of the microbiological intention-to-treat population. In the FDA guidelines, they were also mentioned separately, under clinical microbiology considerations.

Abbreviations: AP, acute pyelonephritis; BPH, benign prostatic hyperplasia; CFU, colony-forming units; cUTI, complicated urinary tract infection; CVA, costovertebral angle; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; uUTI, uncomplicated urinary tract infection.

While the aforementioned research guidelines overlap in the sense that they all include a combination of symptoms and evidence of pyuria and/or bacteriuria in the definition of UTI, they also differ. For instance, none of these guidelines include the same set (or minimum number) of symptoms for the diagnosis of UTI. Moreover, the definition of complicated UTI is variable and based on either systemic signs and symptoms or the presence of host factors predisposing the patient to a complicated clinical course (eg, functional or anatomical abnormalities of the urinary tract).

It is probable that this wide range of possible definitions and different research guidelines pose problems for researchers conducting studies with patients with UTI. A uniform research definition increases homogeneity between studies, which is important for the interpretation, synthesis, and comparability of results, and mitigates the risk of misclassification bias. This is especially relevant in an era of rising antimicrobial resistance, in which novel antimicrobials are being investigated in large randomized controlled trials. The aim of this systematic review is to evaluate how UTI is defined in current studies, and to which extent these definitions differ between studies.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines [ 9 ].

Eligibility Criteria

Studies published between January 2019 and May 2022, investigating any therapeutic or prophylactic intervention in adults with (recurrent) UTI, were eligible for inclusion. Given the fact that definitions tend to change over time, this time frame was chosen to reflect the most recent consensus. In addition, updated FDA and EMA guidelines were published in 2019. We excluded studies concerning only prostatitis, CA-UTI, pericatheter or perioperative prophylaxis, or asymptomatic bacteriuria. Studies investigating patients with spinal cord injury or neurogenic bladder were also excluded, because separate UTI definitions are mostly used for patients who are unable to experience (or have altered perception of) lower urinary tract symptoms. Finally, we excluded systematic reviews, meta-analyses, and studies published in non-English-language journals

Search Strategy

Multiple electronic databases (PubMed, Embase, Web of Science, and the Cochrane library) were searched on 16 May 2022. Our search strategy was constructed by a research librarian and was based on a population, intervention, comparison, outcome (PICO)–style approach. We applied language and publication year filters as described above and used an “article” type filter for clinical trials. The complete search strategy is provided in Supplementary Material 1 .

Data Extraction and Analysis

Covidence software was used for screening and data extraction. References were imported and duplicates were removed. Title and abstract screening, full-text screening and data extraction were performed by 2 independent reviewers (M. P. B. and R. M. H. J.). In case of disagreement, a third researcher was consulted (M. M. C. L.) and a final decision was based on consensus.

For each study, the following data were collected: study design, setting, population, intervention, and the type of UTI under investigation. Criteria for the definition of UTI were subdivided into 3 categories: signs and symptoms, urinalysis, and urine culture. For each of these categories, we assessed whether they were required or conditionally required (ie, dependent on the presence of other categories) for the diagnosis of UTI. If categories were not mentioned, or if they were only required for a secondary outcome or definition, they were considered as not required. Definitions were derived from eligibility criteria unless definitions were explicitly stated elsewhere. For signs and symptoms, additional data were collected on minimum number of symptoms and symptom specification (eg, if fever and frequency were further defined). Moreover, we recorded which symptoms were part of the definition of acute cystitis, acute pyelonephritis, and UTI if a clinical phenotype was not mentioned (henceforth described as UTI–phenotype not specified). For the urinalysis category, we extracted which methods were used for determining pyuria, which cutoff values were applied, and whether nitrites were part of the UTI definition. Regarding the urine culture category, we recorded the cutoff value for colony-forming units (CFU)/mL and the maximum number of uropathogens. For all 3 categories, we assessed whether study definitions met FDA and EMA guideline requirements. Concerning complicated UTI, we collected the same components of the definition as described above, but we also assessed whether the definition was based on host factors, systemic involvement, or a combination of both. Finally, we compared definitions between studies, stratified per UTI type. No risk of bias assessment was performed as we studied definitions instead of outcomes. Data are summarized as proportions.

Study Selection and Study Characteristics

The study selection process is summarized in a PRISMA flowchart ( Figure 1 ). We screened 348 reports published between January 2019 and May 2022. Studies that were excluded during title and abstract screening (n = 290) mainly involved patients with CA-UTI or conditions other than UTI (eg, interstitial cystitis), or investigated pericatheter or perioperative prophylaxis. During full-text screening, 7 non-English articles and secondary analyses of articles already included in the study using our search criteria were excluded. A total of 47 randomized controlled trials and cohort studies with a median of 145 participants were included [ 2–56 ].

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of the study selection process. Abbreviation: UTI, urinary tract infection.

Thirty-one studies (66%) investigated antimicrobials for the treatment of UTI, and 15 (32%) evaluated antimicrobial prophylaxis for recurrent UTI. Sixteen studies (34%) only included women, 4 studies (9%) only included men, and 27 studies (57%) included both. Participants were hospitalized in 25 studies (53%) and treated through an outpatient or primary care clinic in 22 studies (47%). None of the included studies were conducted in LTCFs. Twelve studies (26%) included acute cystitis, 16 (34%) included acute pyelonephritis, and 13 (28%) included UTI–phenotype not specified. A table containing details of all included studies is provided in Supplementary Material 2 .

UTI Definition and Heterogeneity

Table 2 shows how UTI was defined across the included studies. In 11 studies (23%) the definition consisted of only signs and symptoms, in 16 studies (34%) the definition consisted of both signs and symptoms and a positive urine culture, and in 5 studies (11%) all 3 components (signs and symptoms, the presence of pyuria, and a positive urine culture) were required for the diagnosis of UTI. None of the studies investigating acute cystitis (n = 12) or UTI–phenotype not specified (n = 13) included the same set of symptoms and diagnostic criteria in their definition. Of the studies defining acute pyelonephritis, 2 (17%) used identical definitions.

Categories of Urinary Tract Infection Definition

If categories were not mentioned, they were considered as not required. Definitions were derived from eligibility criteria unless definitions were explicitly stated elsewhere. Percentages may not add up to 100 due to rounding.

Abbreviations: CFU, colony-forming units; HPF, high-power field; UTI, urinary tract infection.

Signs and Symptoms

Signs and symptoms were required for the diagnosis of UTI in 40 studies (85%). Of these, 34 (85%) specified signs and symptoms in the definition. The different signs and symptoms that were included in the definition of acute cystitis, acute pyelonephritis, and UTI–phenotype not specified are highlighted in Table 3 . FDA guidelines [ 4 ] require a minimum of 2 of the following symptoms for patients with uncomplicated UTI: dysuria, urgency, frequency, and suprapubic pain. Two of 12 studies (17%) met these criteria. Flank pain and/or costovertebral angle tenderness, fever, nausea and/or vomiting, and dysuria were most often included in the definition of acute pyelonephritis. Frequency was not further specified in any study. Perineal and/or prostate pain was part of the definition in 3 of 31 (10%) studies involving men. A specific temperature cutoff for fever was defined in 7 of 17 (65%) studies that included fever in the definition of UTI.

Symptoms and Signs in Different Types of Urinary Tract Infections

All symptoms and signs are shown as No. (%). Other symptoms mentioned in studies focusing on acute cystitis or UTI–phenotype not specified were vesical tenesmus (n = 1), malodorous and/or cloudy urine (n = 1), hypogastric pain (n = 1), and nocturia (n = 1). Additional criteria for the definition of acute pyelonephritis not mentioned in the table: elevated serum inflammatory parameters (n = 1), signs of pyelonephritis on ultrasound or computed tomography (n = 1), and hypotension (n = 1).

Abbreviations: CVA, costovertebral angle; UTI, urinary tract infection.

This included all studies investigating acute pyelonephritis, either alone or in conjunction with other types of UTI.

Urinalysis and Urine Culture

The presence of pyuria was required for the diagnosis of UTI in 13 of 47 (28%) studies, while both FDA and EMA guidelines [ 3–5 ] require pyuria in their definition of UTI. A cutoff for pyuria was specified in 12 studies, of which 10 (83%) applied a cutoff value of >10 leukocytes/µL or >10 leukocytes per high-power field (HPF). None of the included studies required the presence of nitrites for the diagnosis of UTI, although they were conditionally required in 3 studies (6%). A positive urine culture was mandatory for UTI diagnosis in 26 of 47 (55%) studies, of which 12 (55%) were conducted in the primary care or outpatient setting and 14 (56%) involved hospitalized patients. Of the 19 studies that mentioned a cutoff value for CFU/mL, 8 (42%) used a cutoff of 10 3  CFU/mL. Among all studies, 7 (15%) required a positive urine culture with at least 10 5 CFU/mL, complying with EMA and FDA guidelines [ 3–5 ].

Complicated UTI

We included 14 studies that defined complicated UTI. Three (21%) based their definition on complicating host factors only, 1 (7%) on systemic involvement only, and 9 (64%) on both host factors and systemic involvement. The various host factors included in the definition are provided in Table 4 . Male sex was considered a complicating factor in 2 studies (17%).

Definition of Complicated Urinary Tract Infection

For the purpose of this table, systemic involvement was defined as the presence of fever and/or rigors in the criteria for diagnosis of complicated UTI.

Abbreviations: BPH, benign prostatic hyperplasia; UTI, urinary tract infection.

Host factors were specified in 12 studies; this was used as the denominator for the proportions.

In this systematic review, we demonstrate that UTI definitions used in current research studies are highly heterogeneous in terms of clinical signs and diagnostic tests. In addition, few studies met symptom, pyuria, and urine culture criteria mentioned in existing research guidelines.

The presence of signs and symptoms was required in the majority of UTI definitions used in the included studies. As symptoms and signs remain the cornerstone of UTI diagnosis, it is noteworthy that 15% of studies did not require signs and symptoms for the diagnosis of UTI and an even greater number of studies did not specify which symptoms and signs needed to be present. Defining specific symptoms may help to mitigate the risk of misclassification. Symptom specification is especially relevant in studies involving older patients with UTI, given the high background prevalence of asymptomatic bacteriuria and pyuria [ 57–59 ]. Most of the studies that did clarify which symptoms were part of the UTI definition included classic UTI-associated symptoms such as dysuria, frequency, and urgency. However, we also found a broad variety of nonspecific manifestations, particularly in studies that did not define the UTI phenotype under investigation. Regardless of the unclear clinical relevance of nonspecific symptoms in UTI, this diversity of symptoms contributes to heterogeneity between studies, which is supported by our finding that few of the included studies used the same set of symptoms to define UTI. Furthermore, in over a third of the included reports, a minimum number of symptoms (for diagnosis) was not mentioned. Given the fact that even classic lower urinary tract symptoms are not 100% specific for UTI, and probability of UTI increases when a combination of symptoms is present, a minimum number of symptoms should be specified [ 60 ].

Pyuria and Bacteriuria

Interestingly, less than a third of included studies required the presence of pyuria in the definition of UTI. With the exception of patients with absolute neutropenia and complete obstructive uropathy, pyuria is present in virtually all symptomatic patients with bacteriuria, and its absence has a high negative predictive value for UTI [ 61–63 ]. In the included studies, pyuria was rarely quantified and thresholds for significant pyuria were low. A recent study has shown that low pyuria cutoffs should be avoided in older women, as the specificity for UTI is very low in this population [ 64 ]. Moreover, studies used different units of measurement interchangeably (ie, identical thresholds were applied for cells/µL and HPF), while results are influenced by different (pre)analytical procedures and previous studies have shown a µL-to-HPF ratio of 5:1 [ 65 ]. Be that as it may, quantification of pyuria in UTI studies should be encouraged, and pyuria should be included in the definition of UTI to reduce the risk of misclassification.

As growth of a uropathogen supports the diagnosis of UTI in a symptomatic patient, it is surprising that a positive urine culture was not part of the UTI definition in approximately half of the included studies. Even though urine cultures are not always required in a clinical setting (eg, in primary care), we believe that culture confirmation should at least be encouraged in a research setting. Furthermore, we found that studies used varying cutoffs for significant bacteriuria, ranging from 10 3 to 10 5  CFU/mL, while EMA and FDA guidelines both recommend a threshold of 10 5  CFU/mL. The question remains whether this is the optimal cutoff [ 66 ]; colony counts as low as 10 2  CFU/mL in midstream urine have been found in symptomatic premenopausal woman with Escherichia coli bacteriuria [ 61 , 62 ].

Studies differed widely in their definition of complicated UTI. Since the majority of studies defined complicated UTI based on both complicating host factors and systemic involvement, different clinical phenotypes were included in each study. This not only contributes further to disparities between studies, it also affects the applicability of study results. Moreover, the aforementioned heterogeneity is compounded by the fact that host factors are very diverse in themselves and there is no consensus about which host factors should be included in the definition of complicated UTI. As astutely phrased by James Johnson [ 67 ], “it may be time to find a different term than complicated UTI for UTIs that occur in patients with underlying predisposing factors, since this term seems hopelessly mired in ambiguity.” Johansen et al [ 68 ]. have proposed a UTI classification system for clinical and research purposes based on clinical phenotype, severity, host factors, and pathogen susceptibility. However, this classification system was not used by any of the included studies in our review. In the Netherlands, the primary care guidelines for UTI have already made a distinction between a UTI in a complicated host versus UTI with systemic involvement [ 69 ].

Existing Research Guidelines

We found that few studies met symptom, pyuria, and urine culture criteria mentioned in FDA and EMA guidelines [ 3–5 ]. In addition, we identified that studies more frequently based UTI definitions on clinical practice guidelines. The use of clinical practice guidelines in the place of research guidelines seems inappropriate, as clinical guidelines are less stringent than research guidelines and base empirical treatment recommendations on limited diagnostic information. Taken together, our findings imply that a widely accepted, consensus-based gold standard for the diagnosis of UTI is lacking and is much needed in the field of UTI research.

Strengths and Limitations

Strengths of this systematic review include our comprehensive search strategy, including multiple electronic databases, and extracting data from supplemental material , as UTI definitions were frequently only mentioned in a supplemental protocol. Our study has several limitations. For some of the included therapeutic studies, eligibility criteria served as a proxy for the UTI definition, if a definition was not mentioned separately. This might have contributed to additional heterogeneity. For instance, prophylactic studies including patients with recurrent UTI had more frequently provided separate UTI definitions, since these often served as outcome measures. Also, some heterogeneity might be explained by the fact that we included studies that investigated different UTI phenotypes. However, this effect was mitigated by evaluating different UTI phenotypes separately. Another limitation is that we filtered our search strategy on publication date and study type. While expanding the time period would have provided more data, it would not reflect the most recent consensus and would likely have contributed to further heterogeneity, as these studies were published before the FDA and EMA guidance documents. Furthermore, including more observational studies most likely would not have reduced heterogeneity, as these are presumably less likely to follow FDA and EMA guidelines for drug approval. Since we did not find any recent studies that were conducted in LTCFs, and we excluded studies regarding CA-UTI and UTI in spinal cord injury patients, it is unclear how heterogeneous definitions are in these areas. Defining UTI might be even more challenging for these populations and settings.

UTI definitions differ widely across recent therapeutic and interventional studies. An international consensus-based reference standard is needed to reduce misclassification bias within studies and heterogeneity between studies. To avoid ambiguity, such a reference standard should veer away from the term “complicated UTI” and instead categorize UTI based on systemic involvement, as these are different entities with different treatments. Based on results of this systematic review, our group has initiated an international consensus study to construct a UTI reference standard for research purposes.

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Author contributions. Conceptualization and methodology: M. P. B., R. M. H. J., S. P. C., L. G. V., and M. M. C. L. Screening and data extraction: M. P. B. and R. M. H. J. Data analysis: M. P. B. Writing–original draft preparation: M. P. B. and R. M. H. J. Writing–review and editing: M. P. B., R. M. H. J., C. S., T. N. P., C. N., L. M., J. M. C., S. E. G., B. K., F. W., S. P. C., L. G. V., and M. M. C. L. Supervision: M. M. C. L., S. P. C., and L. G. V. All authors have read and agreed to the final version of the manuscript.

Acknowledgments. The authors thank J. W. Schoones for his contribution to the search strategy.

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Author notes

• urinary tract infections
• heterogeneity
• urine culture
• urinary tract infection, acute

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• Published: 05 October 2023

Prevalence of urinary tract infection and antimicrobial resistance patterns of uropathogens with biofilm forming capacity among outpatients in morogoro, Tanzania: a cross-sectional study

• Eulambius M. Mlugu 1 ,
• Juma A. Mohamedi 1 ,
• Raphael Z. Sangeda 2 &
• Kennedy D. Mwambete 2  

BMC Infectious Diseases volume  23 , Article number:  660 ( 2023 ) Cite this article

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Introduction

Urinary tract infection (UTI) is the second most common infectious disease affecting more than 150 million people globally annually. Uropathogenic E. coli (UPEC), the predominant cause of UTI, can occur as a biofilm associated with antimicrobial resistance (AMR). There is a data gap on global AMR patterns from low-income settings, including Tanzania. Data on antimicrobial susceptibility patterns in relation to biofilm formation will help in the proper selection of antibiotics and the fight against AMR.

This analytical cross-sectional study was conducted among consecutively selected outpatients (n = 344) from January to May 2022 at Morogoro Regional Referal Hospital. Mid-stream urine samples were collected aseptically from symptomatic patients. A significant UTI was defined when more than 10 5 colonies/ml of urine were recorded. Kirby Bauer’s disc diffusion method was used for antibiotics susceptibility patterns and a Congo Red Agar method was used to determine biofilm formation. Two-sided χ2 test or Fisher’s exact test, Cohen’s kappa coefficient and logistic regression were used for data analysis. A p-value < 0.05 was considered statistically significant.

The prevalence of UTIs was 41% (141/344) and elders (>=60 years) had five times higher odds of having UTI as compared to adolescents (p < 0.001). E. coli was the most predominant bacteria (47%; 66/141), which displayed moderate susceptibility against ciprofloxacin (59.1%) and nitrofurantoin (57.6%). A total of 72 (51%) of all isolated bacteria were multi-drug resistant. All isolated bacteria demonstrated high resistance (> 85%) against ampicillin and co-trimoxazole. In this study, 51.5% (34/66) were biofilm-forming E. coli and demonstrated relatively higher antibiotic resistance as compared to non-biofilm forming bacteria (p < 0.05).

We report high antibiotic resistance against commonly used antibiotics. Slightly more than half of the isolated bacteria were biofilm forming E. coli. A need to strengthen stewardship programs is urgently advocated.

Peer Review reports

Urinary tract infection (UTI) is a disease of public health importance affecting more than 150 million people [ 1 ] with a financial burden of about $6 billion worldwide each year [ 2 ]. It is one of the most common infectious diseases, second to upper respiratory tract infections [ 3 ]. More than 50% of all women and at least 12% of men experience UTI in their lifetime [ 4 ]. Data regarding the prevalence of UTI among children and pregnant women are largely available [ 5 , 6 , 7 ], probably because of their susceptibility to secondary complications. Nevertheless, data on UTI prevalence in the general population are scanty in Tanzania indicating the need to regularly monitor the burden of UTIs to inform policy decisions.

For the majority of UTIs, bacteria from the Enterobacteriaceae family are the most frequent culprits. Uropathogenic Escherichia coli (UPEC) are the most prevalent strains causing UTIs, accounting for about 80% of uncomplicated UTIs and about 95% of community and hospital-acquired infections [ 8 , 9 ]. Bacteria colonize the urinary tract by either freely attaching to the epithelial surface (planktonic) reversibly [ 2 ], or forming biofilm [ 10 ] defined by the presence of bacterial aggregates embedded in a self-produced extracellular matrix [ 11 ].

The human immune system has trouble recognizing bacteria and getting rid of infections with biofilm. Additionally, antibiotics penetration to the deeper layers of the biofilm matrix is difficult and may expose bacteria to sub-therapeutic antimicrobial concentrations leading to resistance [ 12 ]. Consequently, biofilm-associated infections tolerate the standard 5–10-day antibiotics treatment [ 13 , 14 ], indicating the need for multi-targeted or combination antibiotics therapies. Availability of data on the biofilm forming patterns in relation to antimicrobial resistance (AMR) may guide the designing of appropriate antibiotics policy guidelines and, eventually, the prevention of AMR. Few studies have reported the relationship between biofilm forming and AMR [ 15 , 16 , 17 ]. However, such data are scarce from Sub-Saharan Africa and Tanzania included [ 18 , 19 ].

Data regarding antimicrobial susceptibility patterns are reported [ 20 ]. However, the patterns of AMR differ across geographical locations and there is data gap in many low-income settings [ 21 ]. The present study investigated the prevalence of UTI in the general population, biofilm forming ability of UPEC and AMR in clinical isolates at Morogoro referral regional hospital, Tanzania.

Study design and setting

This was an analytical cross-sectional study conducted at Morogoro referral regional hospital (MRRH). MRRH is located in the Morogoro region, about 190 km west of Dar es Salaam, the largest business city in Tanzania (Fig.  1 ). The study site choice was motivated by the scarcity of data regarding AMR patterns from the region, which is required for antimicrobial stewardship activities.

Study site map. The top right is the map of the Morogoro region. Bottom right is the map of Morogoro Urban. On the left is the map of Tanzania. The study site map was originally generated using ArcGIS software version 10.7.1 (Esri, California, USA; https://www.esri.uconn.edu/software/arcgis-student/ )

Patient recruitment and data collection

The study targeted all patients attending outpatient clinics with any symptoms of dysuria, urination frequency, urgency, fever, hematuria and suprapubic pain. A standard pilot-tested questionnaire was used to collect patients’ socio-demographic and clinical characteristics. At enrollment, patient’s age, sex, level of education and occupation were recorded. Patients who met the inclusion criteria were conveniently recruited for this study. Outpatients with symptoms unrelated to UTI and those who were admitted were excluded.

Urine sample collection and processing

Urine samples were collected according to the standard procedures as previously described [ 22 ]. For adult participants, the midstream urine method was used and the catch clean method was used for children. Participants were instructed to collect urine samples in two separate sterile containers. One bottle containing the sample was used for the dipstick urine test to detect leucocytes at the study health facility. The other container was immediately stored in the refrigerator (4 °C), where culture was done within 24 h after sample collection [ 22 ].

Isolation of microorganisms

Urine samples were plated on cysteine lactose electrolytes deficient (CLED) agar medium. A loop calibrated to deliver approximately 0.001 mL was used to inoculate urine in CLED agar plates and incubated aerobically at 37 o C for 24 h. The growth of one type of organism of > 10 5 colony-forming units was considered bacteriuria [ 23 , 24 ]. Clinical isolates were identified and confirmed biochemically using standard laboratory workflow [ 25 , 26 ]. Confirmed bacteria isolates were suspended in nutrient broth, supplemented with 16% glycerol, and frozen at -80 o C. The isolated bacteria samples were used for testing antimicrobial susceptibility and biofilm production.

Antimicrobial susceptibility testing

Antimicrobial susceptibility tests were performed according to standards of Clinical and Laboratory Standards Institute (CLSI) guidelines using Kirby ‘Bauer’s disc diffusion method [ 27 ]. Briefly, bacterial suspensions in physiological saline solution were spread platted on Mueller-Hinton Agar. Antimicrobial-impregnated disks, selected based on CLSI, were then placed on the culture medium surface. Commercially available antibiotic sensitivity discs that are widely used in Tanzania, including ampicillin (10 µg), amoxicillin/clavulanic acid (20/10µg), ciprofloxacin (5 µg), co-trimoxazole (trimethoprim/ sulfamethoxazole) (1.25 µg/23.75), ceftriaxone (30 µg), and nitrofurantoin (300µg) were tested. For P. aeruginosa , additional antibiotic sensitivity discs, including imipenem (10 µg), amikacin (30 µg) and gentamicin (10 µg), were also tested. After incubating the plates at 37°C for 18–24 hours, the diameter (nearest whole mm) of the inhibition zones [ 27 ] for each antibiotic was measured. The interpretation breakpoints were based on whether the bacterium was susceptible (S), intermediate (I), or resistant (R) to the tested drugs according to the CLSI recommendations [ 27 ]. Antibiograms were validated using standardized control strains of E. coli (ATCC 25922), S. aureus (ATCC 25923) and P. aeruginosa (ATCC 27853).

Determination of biofilm formation

To detect biofilm forming bacteria isolates, modified Congo red Agar method was used as previously described [ 28 ]. Briefly, bacteria strains were inoculated on blood base agar − 2 (BAB2) (40 gms/L BAB2, 10 gms/L glucose and 1000ml water), with 0.4 gms/L Congo red stain. At first, the Congo red stain was prepared as an aqueous solution and autoclaved (121 °C for 15 min) separately from the other medium constituents. The Congo red solution was added when the agar was cooled and incubated aerobically at 37 °C for 24 /48 hours. Black colonies with a dry crystalline consistency were interpreted as positive biofilm results. A red colored colony indicated negative biofilm results. E. coli ATCC 25,922 was used as positive control and S. aureus ATCC 25,932 as negative control for the CRA method.

Statistical analysis

Statistical package for Social Sciences (SPSS) software (IBM, Armonk, NY, USA) was used to analyze the data. Descriptive statistics (median, IQR, mean + SD, percentages) were used for patients’ socio-demographic characteristics. Comparison between proportions for categorical variables in two independent groups was performed using the two-sided χ2 test or Fisher’s exact test. Cohen’s kappa coefficient was used to test the agreement of positive and negative UTIs between urine deep stick and bacteria culture methods. Multi-drug resistance (MDR) was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories [ 29 ]. Binary logistic regression assessed the association between UTI and independent variables. A p-value < 0.05 was considered statistically significant.

Ethical consideration

The study was approved by the Institutional review board of the Muhimbili University of Health and Allied Sciences (MUHAS) before the commencement of the study (DA.282/298/01.C/920). Permission to conduct the study was requested from the Morogoro regional referral hospital’s medical officer in charge. Written consent was obtained from all participants before enrollment.

Socio-demographic characteristics of participants

A total of 344 patients attending the outpatient clinic presenting with UTI symptoms were recruited for this study from January to May 2022. Participants had a median age of 25.5 (1–83) years; the majority (63%) were young adults between 19 and 59 years old. About three-quarters of the participants (76.4%) were women. More than half of the female adults were pregnant (60%). Almost half of the adult participants (52.1%) had formal employment and three quarter (66.7%) were living with a partner. The socio-demographic characteristics of participants are shown in Table  1 .

Prevalence and determinants of UTI

The prevalence of UTI among patients attending the outpatient clinic presenting with UTI symptoms was 34.3% (118/344) and 41% (141/344) by dipstick urine analysis and culture, respectively. There was low agreement between dipstick urine analysis and culture in detecting positive UTI (Kappa = 0.11). The sensitivity and specificity of dipstick urine analysis were 43% and 69%, respectively, compared to the urine culture method.

The relationship between baseline parameters and the prevalence of UTI was evaluated. There was no significant difference in UTI prevalence between different levels of education (p = 0.13), marital status (p = 0.37) and occupation (p = 0.77). When comparing pregnant with non-pregnant adult women, there was no statistically discernible difference in the prevalence of UTI (p = 0.40). On logistic regression, elderly patients (≥ 60 years) had five times higher odds of having UTI as compared to adolescents. Female participants had almost two times higher odds of having UTI as compared to male participants at the borderline p  = 0.05 (Table  2 ).

Antimicrobial susceptibility patterns

UPEC was the most common isolated bacteria, accounting for 47% (66/141) of all the isolated species. P. aeruginosa, K. pneumoniae and P. mirabilis contributed 17% (24/141), 11.4% (16/141) and 14.2% (20/141) of all isolated species, respectively. Other species, which were non-identified Gram negetive bacilli, accounted for 9.9% (14/141).

A total of 72 (51%) of all isolated bacteria demonstrated resistance to at least one agent in three or more antimicrobial categories (MDR) Fig.  2 . For P. aeruginosa , MDR was assessed in three antimicrobial families namely aminoglycosides (amikacin and gentamicin) flouroquinolones (ciprofloxacin) and carbapenems (imipenem). Isolates of P. aeruginosa displayed low rates of MDR, which differed significantly compared to other isolated bacteria (Fig.  2 ).

Proportion of MDR among the isolated bacteria species. Other species represent non-identified Gram negetive bacilli ( p- value is based on the Chi-Square test)

Isolated species demonstrated moderate to low susceptibility to the tested antibiotics. E. coli showed fairly susceptibility against ciprofloxacin (59.1%), nitrofurantoin (57.6%) and ceftriaxone (50%). P. aeruginosa displayed the highest susceptibility against amikacin (87.5%) and imipenem (83%) and lower susceptibility against gentamicin. K. pneumonia demonstrated fair susceptibility against ciprofloxacin (50%). Figure  3 presents the AMR patterns for the isolated species.

Antimicrobial resistance patterns among isolated bacteria ( ` n´ indicate the number of isolates under each bacteria specie)

Biofilm formation

The black colonies, with a dry crystalline consistency, were interpreted as positive biofilm results. In contrast, red colored colonies indicated negative biofilm results (Fig.  4 ). Of the 66 clinical isolates of E. coli , 34 (51.5%) formed biofilm on CRA.

Congo Red Agar plates showing non-biofilm forming (A = red colored colonies) and biofilm forming (B = Dry crystalline Black colonies) UPEC isolates

More biofilm forming UPEC were MDR compared to UPEC non-biofilm forming isolates, although the difference was not statistically significant (p-value = 0.17). On the other hand, biofilm forming isolates demonstrated significantly higher resistance against co-trimoxazole and amoxycillin/clavulanic acid (p < 0.05), as shown in Table  3 .

UTI is a public health problem accounting for more than 15% of all the antibiotics prescriptions among outpatients [ 30 ]. Infections forming biofilm are associated with AMR and recurrent UTIs [ 31 , 32 ] both of which are currently increasing globally [ 4 ]. Nevertheless, data regarding the characterization of biofilm-forming UTIs in relation to AMR rates in sub-Saharan Africa are scanty. We report, a substantial proportion of outpatient clinic patients with UTI symptoms had UTI, high AMR rate to commonly used antibiotics and 50% of UPEC isolates forming biofilm UTI associated with antibiotics resistance. The study included an outpatient population presenting with UTI symptoms regardless of sex and age to reflect the real-world population distribution. To the best of our knowledge, this is the first study to report biofilm-forming patterns of UPEC and their correlation with antibiotics resistance from Tanzania.

In this study, 41% of patients attending the outpatient clinic with any UTI symptoms were found to have culture-positive UTI. This prevalence is higher than the global prevalence, which ranges from 13 to 33% but is comparable to that of other resource-limited countries [ 33 ]. Our finding is also relatively lower than that reported among children with symptoms attending pediatric clinics [ 34 ] and among women attending outpatient clinics (63%) [ 35 ] in Dar es Salaam, Tanzania. On the other hand, our finding is higher than that reported among symptomatic women in Mwanza, Tanzania (18%) [ 36 ] and among asymptomatic pregnant women in Arusha (31.6%) northern part of Tanzania [ 37 ]. Our results indicate the diverse burden of UTI across different geographical locations, which might explain the differences in social determinants of UTI.

This study found a higher prevalence of UTI in women than men at the borderline (p = 0.05). Usually, women have shorter urethra, which is close to the perineum, than men; thus, they are more prone to UTI than men [ 38 ]. The fact that there were fewer male participants in the current study may account for the lack of significant differences. In contrast, older people had a considerably higher chance of getting a UTI than teenagers, which could be attributed to immunosenescence, an age-related immunological shift [ 39 ]. Other baseline characteristics did not show a significant effect on UTI.

Isolated species exhibited moderate to high resistance patterns against commonly used antibiotics. Half of all isolated bacteria species were resistant to at least one agent in more than two classes of antibiotics, referred to as multi-drug resistance (MDR). All isolated species showed high resistance rates against co-trimoxazole and ampicillin, similar to other reported findings from previous studies [ 40 ], suggesting that the drugs might have limited susceptibility against UTI and should be less considered in the treatment regimen. E. coli was the most predominant isolated species and displayed moderate resistance rates against ceftriaxone (34%), ciprofloxacin (37%) and nitrofurantoin (37%) which is comparable to several other previous studies [ 41 , 42 ]. On the contrary, previous studies reported a higher resistance rate against ceftriaxone, ciprofloxacin and nitrofurantoin [ 36 ] [ 43 ]. Ciprofloxacin and ceftriaxone are the drugs of choice for UTI in Tanzania, suggesting that a substantial proportion of UTIs from the setting may be susceptible to the first-line antibiotics. However, isolated species exhibited high resistance against amoxicillin/clavulanic acid, the drug of choice for UTI in pregnant and adolescent women [ 44 ], similar to a previous study from Uganda [ 45 ].

P. aeruginosa demonstrated the highest sensitivity rates (> 80%) against amikacin and imipenem with low rates of MDR. The reason for this finding could be that these are reserved antibiotics and not commonly used in health facilities thus, they have low chances for resistance development. On the contrary, P. aeruginosa showed a higher rate of resistance (85–100%) among the commonly used antibiotics corroborating the findings of previous studies [ 46 ]. The finding implies that most UTIs associated with P. aeruginosa may not respond to commonly prescribed antibiotics. Our findings contribute to the knowledge about antibiotic resistance patterns peculiar to this geographical location.

About half of isolated E. coli were biofilm formers on Congo Red Agar (CRA). This finding suggest that biofilm forming UTIs are common in Tanzania similar to the findings of previous studies from other regions [ 15 , 16 , 17 ]. The susceptibility pattern showed that biofilm-forming E. coli were more MDR (60%) compared to non-biofilm formers (40%). Although statistical significance was not reached for the overall MDR, biofilm formers showed significantly higher resistance rates against ciprofloxacin and co-trimoxazole as compared to non-biofilm formers. Previous studies from other regions reported significant association between biofilm forming capability and AMR for the same antibiotics as the present study [ 15 , 16 , 17 ]. One reason to explain this might be the difficult penetration of antimicrobials to the deeper layers of the biofilm matrix which expose bacteria to sub-therapeutic antimicrobial concentrations leading to resistance [ 12 ]. This finding informs the policy makers on the importance of considering the impact of biofilm infections in policies against antimicrobial resistnance.

The observed high antibiotic resistance patterns might be explained by the community´s inappropriate and overuse of antibiotics [ 47 ]. Miserably, AMR causes a stall in achieving the global sustainable development goal number 3.3, which aims at reducing the burden of infectious diseases by the end of 2030 [ 48 ]. The findings of this study underscores the need for strenghthening antimicrobial stewardship in health facilities [ 49 ].

UTI is treated empirically in Tanzania and other resource-limited countries. In the majority of primary healthcare facilities, urine analysis is based on dipstick urine analysis, which in this study was found to have a lower sensitivity (45%) than urine culture. This suggests that a method used in the standard of care for diagnosing UTIs may miss a considerable portion of individuals who have severe bacteriuria. The findings underscore the need for integrating urine culture and sensitivity to properly manage UTI in our health facilities.

Conclusion and recommendations

We report a high prevalence of culture-positiveUTI among outpatients presenting with UTI symptoms from the study population. High prevalence rates of antibiotic resistance were also observed in clinical bacterial isolates. Slightly more than half of the isolated E. coli bacteria were biofilm forming, demonstrating higher antibiotic resistance to co-trimoxazole and amoxicillin/clavulanic acid than non-biofilm forming counterparts. A need to strengthen AMR stewardship programs in health facilities is urgently advocated in order to halt the spread of AMR.

Data Availability

All data generated or analyzed during this study are included in this manuscript.

Abbreviations

Clinical and laboratory standards institute

Multi drug resistance

Standard Operating procedures

Uropathogenic E. coli

Muhimbili University of Health and Allied Sciences

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Acknowledgements

We convey our sincere thanks to all participants who took part in this study. We also thank the Pharmaceutical Microbiology Laboratory (MUHAS) staff for their support during experiments.

This work was funded by the Muhimbili University of Health and Allied Sciences through seed grants supported by the Swedish International Development Cooperation Agency– (Sida). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.

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EMM designed the study performed the data collection and wrote the frist draft of the manuscript; EMM, JAM, RZS and KDM participated in data analysis. All authors read, edited and approved the final manuscript.

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Mlugu, E.M., Mohamedi, J.A., Sangeda, R.Z. et al. Prevalence of urinary tract infection and antimicrobial resistance patterns of uropathogens with biofilm forming capacity among outpatients in morogoro, Tanzania: a cross-sectional study. BMC Infect Dis 23 , 660 (2023). https://doi.org/10.1186/s12879-023-08641-x

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Deep insights into urinary tract infections and effective natural remedies

• Bibi Sedigheh Fazly Bazzaz 1 , 2 ,
• Sareh Darvishi Fork 3 ,
• Reza Ahmadi 4 &
• Bahman Khameneh   ORCID: orcid.org/0000-0002-0595-7667 2  

African Journal of Urology volume  27 , Article number:  6 ( 2021 ) Cite this article

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Urinary tract infection (UTI) is a common occurrence in females, during pregnancy, and in peri- and postmenopausal women. UTIs are associated with significant morbidity and mortality, and they affect the quality of life of the affected patients. Antibiotic therapy is an effective approach and reduces the duration of symptoms. Development of resistance, adverse effects of antibiotics, and other associated problems lead to establishing the research framework to find out the alternative approaches in controlling UTIs. Natural approaches have been extensively used for the management of various diseases to improve symptoms and also improve general health.

Different databases were employed to identify studies reporting on natural options including herbal medicines, vitamins, trace elementals, sugars, and probiotics without time limitations.

Herbal medicines can be effective at the first sign of the infection and also for short-term prophylaxis. Using vitamins, trace elementals, and/or sugars is an effective approach in preventing UTIs, and a combination of them with other antibacterial agents shows positive results. Probiotics have great potential for the threat of antibiotic over-usage and the prevalence of antibiotic-resistant microorganisms. This study may be of use in developing the efficient formulation of treatment of UTI.

1 Background

Urinary tract infection (UTI) is one of the most prevalent bacterial infections in women and elderly individuals. This type of infection although can cause less severe life-threatening infections but the patient experienced significant distress [ 1 ]. Additionally, this infection is associated with substantial healthcare and societal costs which is only in the USA; UTIs are responsible for 7 million clinic visits annually [ 2 ]. Except among infants and the elderly, the infection occurs more commonly in women than in men and it was estimated that about 40–50% of women experience one episode in their lives and 20–30% of them have other episodes [ 3 ]. For women between 1 year and up to 50 years, UTI and recurrent UTI (rUTI) are predominantly diseases [ 3 ]. rUTI is mainly associated with abnormalities of the urinary tract detected after kidney transplantation or also secondary to end-stage renal disease. Moreover, a significant proportion of patients who develop rUTI have no identifiable causes [ 4 ].

UTI is mostly caused by bacteria, through other microorganisms such as fungi and viruses that are rare etiologic agents [ 5 ]. This type of infection can be classified as complicated or uncomplicated. Uncomplicated UTI is the most common type of infection and mainly occurs in the absence of functional or anatomical abnormalities within the urinary tract. The complicated one occurs in the presence of an abnormal urinary tract that increases susceptibility to infection [ 1 ].

Among the uropathogen, Escherichia coli is the most common bacteria (75–90% of isolates) in both the community and hospital infections, whereas other pathogenic bacteria such as Proteus mirabilis , Staphylococcus saprophyticus (with particularly frequent isolation from younger female), Enterococcus faecalis , Klebsiella pneumoniae , and Pseudomonas aeruginosa each are less important [ 1 , 2 , 3 ]. The uropathogenic bacteria express fimbrial adhesions that they attach to the glycolipids and glycoproteins on the epithelial surface. In this way, bacteria can overcome the flow of urine and maintain in the urinary tract. The bacteria also produce other substances such as toxins, hemolysin, and colony-necrotizing factors. These agents disrupt epithelial integrity, permit bacterial invasion, and, therefore, enhance the risk of infection [ 6 ]. Uropathogens also can internalize into host epithelial cells and divide inside there, so that it provides a reservoir for recurrent infection [ 1 ].

In most cases, these uropathogens begin to colonize the surface of the perineum and periurethral and precede the development of infection. Colonization of bacteria could be inhibited by the normal microbiota, such as Staphylococcus epidermidis , Lactobacillus spp, and Corynebacteria [ 7 ]. Additionally, bacterial colonization and initial infection were eliminated by host defense mechanisms in the bladder. The foreign bodies such as urinary catheters or stone in the urinary tract provide an inert surface for bacterial colonization [ 3 ].

Female anatomy, age, sexual activity, certain types of birth control, and menopause are the most risk factors for UTI. Other risk factors are urinary tract abnormalities, blockages in the urinary tract, suppressed immune system, catheter use, and a recent urinary procedure [ 8 ].

Several types of antibiotics have been used to treat UTIs. Antibiotic therapy is an effective approach and reduces the duration of symptoms. Empirical treatment is usually with 3 days of antibiotics which achieves a cure in 85–90% of women. This type of regimen is equivalent to longer regimens and also is more effective than a single-dose administration [ 1 , 9 ]. Various regimens have been used to treat UTI; for men, quick antibiotic therapy for at least seven days is recommended. In the patients treated in the first line, the administration of trimethoprim and nitrofurantoin is currently used. Second-line antibiotics such as quinolones should be considered for patients with prostatitis [ 10 ]. NHS Clinical Knowledge Summaries recommend various antibiotic therapy regimens: (1) seven days of ciprofloxacin, co-amoxiclav, or cephalexin or (2) 14 days of trimethoprim for men and non-pregnant women, and (3) 7–10 days of cefalexin for pregnant women. Severe infections require hospital care and treatment with broad-spectrum parenteral antibiotics and admission for intravenous fluids.

In the last decades, the extensive use of antibiotics has resulted in the emergence of antibiotic-resistant bacterial pathogens and leads to the spread of antibiotic resistance. Additionally, because of the chronic nature of UTIs and the potential for antibiotic resistance, a promising approach to prevention and treatment is favorable. These days various approaches have been developed to overcome the problems associated with antibiotic resistance [ 11 , 12 , 13 ]. Complementary and alternative medicine (CAM) has been recognized as an effective approach for the treatment of infection by antibiotic-resistant bacteria [ 11 , 14 , 15 , 16 ]. CAM consists of a wide range of products such as natural compounds, dietary supplements as vitamins and minerals, and also probiotics [ 17 ]. This type of medicine has been attracted great attention in modern countries. For example, according to statics, 1.8% of children in the USA are treated with CAM. However, the real frequency of CAM is estimated higher than this amount. Clinically research suggests the best natural options for long-term prevention include probiotics, medical herbs, vitamins, and elements that have also been shown to prevent UTIs [ 18 , 19 , 20 ]. So, we could hope that using CAM in the treatment of UTI could provide desirable results, especially when combined with a routine antibiotic regimen. In the present review, the most important classes of the compound which have been used in CAM are mentioned. By using these natural remedies along with conventional antibiotic therapies, better results were obtained.

2 Main text

This review was based on data extracted from published papers with the search terms of urinary tract infection, herbal medicine, vitamin, probiotics, supplements, and antibacterial resistance which are available in all relevant databases, especially PubMed, Web of Science, Scopus, MEDLINE, and EMBASE, without limitation up to August 1, 2020.

2.1 Herbal medicine

In recent years, the use of medicinal herbs in the prevention and treatment of various diseases has been increased [ 13 , 21 ]. Complimentary therapy with medicinal herbs is a research area that may be deserving of special attention. The complementary therapy of antibiotics with medicinal herbs showed mainly synergistic effects [ 11 ]. In many studies, herbal medicines could reduce bacterial resistance to antibiotics, remarkably [ 15 , 16 ]. So, in many cases, patients may benefit from this type of therapy. It was shown that herbal medicines could play an important role in the treatment of a type of UTI [ 22 ]. Since several plant antimicrobial compounds contain various functional groups in their structure, the antimicrobial activities are attributed to multiple mechanisms [ 13 ]. The chemical compounds presented in herbal medicines evolved to protect the plant from pathogenic microorganisms and therefore could prevent or treat infections in animals. Many of these compounds are renally excreted so that they are specifically useful as urinary antiseptic agents. Two major mechanisms are involved in the antimicrobial properties of these compounds. Some of them directly kill microbes and some of them interfere with microbial adhesion to epithelial cells [ 23 ]. These herbs play an important role in assisting to resolve UTI. Here, we briefly review the role of medicinal herbs and their variant in the treatment of infections. Some of these herbal medicines with more details are illustrated in Fig.  1 .

Used herbal medicines in the treatment of UTI. The active constituents with the related mechanism of action(s) are also described

2.1.1 Arctostaphylos uva-ursi

Arctostaphylos uva-ursi (bearberry) is a plant species of the genus Arctostaphylos. The leaves of this plant have been traditionally used because of their diuretic properties [ 23 ]. The plant has been used for the treatment of infectious diseases, especially for UTIs. The herb is approved in Germany for the treatment of bladder infections and effective against E. coli in the bladder [ 24 ].

The leaves of the plant are responsible for the therapeutic actions which contain the glycoside arbutoside. This compound is hydrolyzed in the bowel to glucose and the aglycone hydroquinone which is absorbed and glucuronidated in the liver. Hydroquinone glucuronide is then carried to the kidneys and excreted in the urine. In the alkaline condition of urine, the hydroquinone glucuronide will decompose automatically and hydroquinone which is worked as a direct antimicrobial agent will be released [ 23 ].

It should be noted that based on information from laboratory researches exposure to synthetic hydroquinone for the long-term may be carcinogenic, so that it is recommended the consecutive consumption of this herbal medicine should not be extended more than two weeks.

Tannins presented in this plant could potentiate the in vitro antibacterial activities of β-lactam antibiotics against methicillin-resistant S. aureus (MRSA). Consequently, due to that whole plant extracts contain other constituents that increase antibacterial activities, it is recommended to use whole plant extracts instead of isolated arbutoside.

2.1.2 Juniperus communis

Juniperus communis (juniper), which belongs to the Cupressaceae family, and other closely related species including Juniperus monosperma (Engelm) Sarg and Juniperus osteosperma (Utah juniper) show remarkable antimicrobial activities [ 25 ]. It was reported that terpenoids in the leaf of the herbs are responsible for the antibacterial and diuretic activities of the herbs [ 23 ]. Schilcer reported that Juniper oil was effective against urinary tract infections [ 26 ]. Leaf and berries of the plant show antimicrobial activities against urinary tract infections. The main antibacterial constituent of this plant is terpinen-4-ol, a volatile oil, which plays an important role in the treatment of UTIs [ 27 ]. This plant also contains other active agents such as oxygenated sesquiterpene, β-pinene, sabinene, monoterpene hydrocarbons, limonene, and myrcene [ 22 ]. It should be noted that the volatile oil of juniper contains nephrotoxic compounds, especially hydrocarbon terpenoids. However, these adverse effects might only be seen after receiving high doses which far exceeded the therapeutic dose [ 23 ].

It was indeed previously demonstrated that the extracts presented diuretic activity [ 27 ]. The juniper leaf infusions show more diuretic activity than the volatile oil, which suggests that other constituents contribute to the diuretic activity of the herb.

2.1.3 Vaccinium macrocarpon (cranberry)

Many researchers have suggested that cranberry is active against UTIs. The plant belongs to Ericaceae family and can be potentially active against E. coli , the leading causes of bacteria-mediated UTIs, by reduction of bacterial attaching to the walls of the bladder, and then, the bacteria are more likely to be washed out during urination. Cranberry juice intake leads to measurable protection against both sensitive and resistant strains of E. coli [ 28 ]. It could also inhibit the binding of bacteria to gastrointestinal mucosa [ 29 ]. It was shown that cranberry juice consumption reduced the biofilm formation of both Gram-negative and Gram-positive uropathogens [ 30 , 31 ].

Cranberry contains proanthocyanidins, which are stable phenolic compounds and contribute to the anti-adhesion activity against E. coli . Also, the in vitro antibacterial activities of cranberry extracts and juice against other pathogens such as S. aureus , P. aeruginosa , K. pneumoniae , and P. mirabilis have been previously demonstrated [ 32 ]. Cranberry proanthocyanidins mainly contain A-type and B-type linkages, while in comparison with B-type linkage, A-type linkage is more effective in preventing adhesion of P-fimbriated uropathogenic E. coli to uroepithelial cells of the bladder and responsible for anti-adhesion activities of the extract, therefore inhibiting the ability of E. coli to infect the urinary mucosa [ 33 , 34 ].

Cranberry also contains other biologically active constituents such as anthocyanidin, catechin, flavanols, myricetin, quercetin, and phenolics which are supposed to be responsible for its activities [ 35 ].

The other possible mechanism of action of cranberry might be related to acidification of the urine; however, it only causes temporary effects, and the changes last about 15 min in most people. Therefore, this mechanism could not be of relevance.

Due to these health benefits of cranberry extract, different commercial formulations of the extract exist in the market. In acute situations, the usual dose of the juice is 250–500 ml two to three times daily and for prevention consumption of 250–500 ml per day is enough. The solid dosage forms such as capsules that contain concentrated cranberry extract are also available. In acute situations, taking 2–3 capsules two to four times per day and taking 1 two to three times daily for prevention are recommended [ 36 ].

In summary, the existing data indicate the beneficial effects of cranberry preparations against UTIs; however, these effects are mainly related to prophylactic activities by preventing the development of infections or in combination with conventional antibiotics and solely intake of the herb is not recommended for UTI treatment.

2.1.4 Vaccinium myrtillus (Blueberry)

Blueberry has extensively been used traditionally to treat and prevent UTI. Blueberry extracts contain similar constituents as cranberry extracts, and the extracts possess similar anti-adhesive activities against uropathogenic bacteria and the bacteria are significantly less able to adhere to the walls of the bladder [ 24 , 37 ]. Tannins are the most active constituents of blueberry extracts against UTI.

2.1.5 Cinnamomum verum (Cinnamon)

Cinnamon belongs to the Lauraceae family and shows antioxidant and antibacterial activities. It contains bioactive phytochemical compounds such as trans-cinnamaldehyde, eugenol, trans-cinnamyl acetate, and proanthocyanidins which have been used in the treatment of UTI.

Amalaradjou et al. showed that trans-cinnamaldehyde as an essential oil was able to inhibit biofilm formation of E. coli on urinary catheters by downregulating major virulence genes in the bacteria.

Various mechanisms are involved in antibacterial activities of essential oils: (I) due to their hydrophobicity, these molecules could target the lipid-containing bacterial cell membrane and mitochondria and alter the permeability which finally leads to leakage of ions and other cell contents, (II) inhibiting energy generation and glucose uptake, and (III) inhibiting activities of important enzymes such as amino acid decarboxylases [ 38 ].

2.1.6 Agathosma betulina (buchu)

A. betulina is one of the oldest known herbs for the treatment of uncomplicated UTI [ 39 ]. The leaves of the herb contain various phenolic compounds and have been used as an herbal remedy for urinary tracts, because of the diuretic and antiseptic properties. In a study, it was demonstrated that the ethanolic leaf extract of A. betulina showed antibacterial activities against E. coli , K. pneumoniae , P. mirabilis , P. aeruginosa , S. aureus , Staphylococcus saprophyticus, and E. faecalis [ 40 ]. For a preparation containing the leaves extract of A. betulina , the anti-adhesive properties were investigated, and the results showed the anti-adhesive effects of the preparation by interacting with T24 cells [ 41 ].

2.1.7 Hybanthus enneaspermus

H. enneaspermus was studied to evaluate the in vitro antibacterial activity of various types of extracts against the major UTI including E. coli , P. aeruginosa , K. pneumoniae , P. mirabilis , E. faecalis, and S. aureus . Among the extracts, ethanol extract showed the most antibacterial activities against the pathogens. The extract has various bioactive compounds such as flavonoids, terpenes, phenolic, and alkaloids that the therapeutic values are attributed to the presence of them.

2.1.8 Armoracia rusticana (horseradish)

A. rusticana (synonyms: Cochlearia armoracia , Radicula armoracia ), which belongs to the family Brassicaceae , traditionally has been used to treat UTI. It shows favorable results for the prevention of recurrent UTI in pediatric patients [ 42 ]. It was demonstrated that the isothiocyanates of horseradish are responsible for their antibacterial activities of the herb. It was shown that these bioactive compounds could block the pathogenic process of human cell penetration by uropathogenic E. coli [ 43 ].

2.1.9 Hydrastis canadensis (Goldenseal)

H. canadensis (Goldenseal) has been used traditionally to treat various diseases such as digestive disorders, UTI, and skin diseases and also to check internal hemorrhage [ 44 ]. The rhizome, rootlets, and root hairs of the herb produce bioactive alkaloids and isoquinoline alkaloids [ 45 ]. These bioactive compounds may act similarly to proanthocyanidins, which are found in cranberry, in inhibiting bacteria from sticking to the bladder walls [ 24 ].

Berberine is a bioactive herbal alkaloid which presents in various medicinal plants such as H. Canadensis , Berberis aquifolium , B. vulgaris , and B. aristata [ 13 ]. This compound has been used in the treatment of UTI [ 46 ]. Notably, berberine exerts its antibacterial activities against UTI with interfering adhesion of E. coli to bladder epithelium.

2.1.10 Equisetum arvense (Horsetail)

E. arvense (Horsetail) is one of the oldest and most famous herbal medicine. The plant has a vast variety of therapeutic properties such as antibacterial activities [ 47 , 48 ]. It was shown that the ethanol extract of the herb showed antibacterial activities against urinary tract pathogens including E. coli , K. pneumonia , P. mirabilis , P. aeruginosa , S. aureus , S. saprophyticus, and E. faecalis . The commonly known phytochemical compounds from Horsetail are alkaloids, phytosterols, tannin, triterpenoids, and phenolics [ 49 ]. Among them, phenolic compounds, especially flavonoids, present in the plant extracts are responsible for the antibacterial activities [ 50 ]. The essential oil of the herb was shown to possess broad-spectrum antimicrobial activities against tested strains.

2.1.11 Urtica dioica (nettle)

U. dioica (nettle) is a perennial plant of the Urticaceae family and has been traditionally used for the treatment of various diseases such as arthritis, rheumatism, UTI, kidney stones, and gingivitis [ 51 ].

It was shown that the plant extracts exhibit antimicrobial activities against various Gram-positive and Gram-negative bacteria such as Bacillus subtilis , Lactobacillus plantarum , P. aeruginosa , E. coli , K. pneumoniae , S. aureus, and S. epidermidis [ 52 ]. The leaf of the herb is a valuable source of biologically active compounds that show antimicrobial activities and could be used to treat infectious diseases [ 53 ].

It should be noted that the role of nettle in the treatment of UTI might be due to the diuretic activities of the herb [ 54 ].

2.1.12 Plantago major L.

P. major L. belongs to the Plantagináceae family and is used traditionally for the treatment of several diseases such as infectious diseases, pain relief, and reducing fever. The major chemical compositions of the herb include mucilage, organic acids, polysaccharides, and flavonoids. The herb traditionally has been used in Iran for pulmonary infections, stomach ulcers, and infections [ 55 ].

2.1.13 Other herbs

The essential oil of Salvia officinalis showed inhibitory activities against clinically isolated uropathogens [ 56 ]. Barosma betulina has been used traditionally for the treatment of various diseases such as UTI, catarrhal cystitis, and urethritis. The in vitro studies showed its antimicrobial effects against uropathogens. Other herbs that have been used for the treatment of UTIs but are not yet adequately studied include Mentha piperita , Allium sativum , Terminalia chebula , Taraxacum officinalis, and Zingiber officinale [ 22 ].

2.2 Nutrition therapy

Using nutrients is an integral part of the management, prevention, and treatment of UTIs. In most cases, micronutrients have been used to this end and they are included vitamins and minerals in general. The role of each agent in the prevention or treatment of UTIs is illustrated in Fig.  2 .

The role of nutrition therapy in the prevention and treatment of UTIs. The ingredients with the related mechanism of action(s) are also described

2.2.1 Vitamins

Vitamin C possesses antimicrobial activities and is frequently used as an important supplement to antibiotic therapy for UTI [ 57 ]. Vitamin C is considered as a non-enzymatic antioxidant that slows down the production of free radicals and oxidation, which leads to strengthening the immune system and the deficiencies of vitamin C could place the persons at risk for infections due to the negative impacts on immune function [ 58 ]. Various studies have been conducted to show the efficacy of vitamin C in the management of UTIs. Yousefichaijan et al. studied the efficacy of vitamin C supplementation on UTI in children for 14 days. The results showed that vitamin C supplementation was able to control the symptoms of UTI, including dysuria, fever, urinary urgency, and also dribbling urine [ 59 ]. Ochoa et al. investigated the role of a daily intake of vitamin C for its effect on UTIs during pregnancy. They showed that daily usage of vitamin C has significant effects on the reduction of UTIs and also improving the health level of the women [ 60 ]. The formation of struvite stones is associated with UTIs by urease-producing bacteria. It was shown that the vitamin can modulate the struvite crystal formation in the presence of uropathogenic bacteria [ 61 ]. In another study, the combination of cranberries, a probiotic ( Lactobacillus rhamnosus ), and vitamin C has been used to evaluate the clinical benefits due to their additive or synergistic effects. The results showed that the approach might represent a safe and effective option in UTI management [ 62 ]. It was shown that nitrite may be generated by bacteria in urine during UTI. Acidification of nitrite leads to the formation of nitric oxide (NO) and other reactive nitrogen oxides that are toxic for a wide range of microorganisms. In a study, NO formation and bacterial growth in mildly acidified urine containing nitrite and vitamin C as a reducing agent were investigated. The growth of bacteria was markedly reduced by the addition of nitrite to acidified urine. Additionally, the inhibition was enhanced by vitamin C. These results help to explain the bacteriostatic effects of acidified nitrite because of the release of NO and other toxic reactive nitrogen intermediates and also the role of vitamin C in the treatment and prevention of UTI [ 63 ].

The positive role of vitamin A supplementation in the prevention and treatment of UTI has been mentioned previously [ 64 ]. Vitamin A has been used in the management of UTIs in children. The results of the study indicated that in the group of the children who received 200,000 IU of the vitamin in combination with antibiotics, the incidence of UTIs was lower than the control group [ 65 ]. In another study, vitamin A supplementation in addition to antimicrobial therapy was used to improve UTI symptoms and preventing renal scarring in girls who suffer from acute pyelonephritis. The results showed that vitamin A supplementation is an effective approach for improving the clinical symptoms of UTI and also reducing the renal injury and scarring following acute pyelonephritis [ 66 ]. Sobouti et al. studied the effects of vitamin A or E supplementation in addition to antimicrobial therapy for the prevention of renal scarring in acute pyelonephritis. According to the results, vitamins A or E supplements were effective in reducing renal scarring secondary to acute pyelonephritis [ 67 ]. The other study was conducted to determine the effect of vitamin A supplementation on the rate of permanent renal damage in children with acute pyelonephritis. It was demonstrated that the administration of vitamin A leads to a significant reduction in permanent renal damage [ 68 ].

Different mechanisms have been mentioned for the implication of vitamin D on the management of UTI. It was shown that tight junction proteins play important roles in preventing the bacterial invasion of the epithelial barrier and supplementation with vitamin D could strengthen the urinary bladder lining and restore the bladder epithelial integrity [ 69 ]. Additionally, on the one hand, vitamin D could act as a local immune response mediator in UTI and on the other hand, enhancing vitamin D levels leads to modulate the innate immune system and provides a protective response to infection [ 70 , 71 ]. The relation between the status serum level of vitamin D and the risk of UTI has been studied extensively, and the results showed a significant association between increased risk of UTI and vitamin D insufficiency, as an independent risk factor, especially in children [ 72 , 73 , 74 ]. Women with vitamin D deficiencies show a higher risk level of UTI during pregnancy [ 75 ]. Vitamin D deficiency is common and the proven risk factor for UTIs especially in girls and supplementation with vitamin D could prevent first-time UTI [ 76 ]. In a randomized clinical trial, the subjects who received vitamin D3 (20,000 IU per week) for five years showed better prevention against UTI [ 77 ]. Together, these results demonstrate that vitamin D supplementation provides a potent weapon in the prevention of UTI.

2.2.2 Minerals

The role of zinc in the management of the infectious disease has been described extensively [ 17 , 78 ]. It was shown that the element increases the response to treatment in many infections and active against different pathogens such as E. coli , Mycobacterium tuberculosis , Salmonella typhi, and Streptococcus pyogenes [ 79 , 80 , 81 ]. The incidence of zinc deficiency in infectious disease clinics has been reported extensively [ 82 , 83 ]. The results of the Mohsenpour et al. study showed that serum zinc levels in people with recurrent UTI were lower than those in the control group. So, the zinc level could be assumed as a risk factor for recurrent UTI [ 84 ]. In another study, the relation between serum zinc levels in children inflicted with UTI and the control group was assessed. According to the data, lower zinc levels were associated with susceptibility to UTI, and therefore, zinc administration has been suggested [ 85 ].

Microbial infections are often associated with selenium deficiencies. The main physiological properties of this micronutrient are directly attributed to its presence within selenoproteins [ 11 ]. Selenium at a certain concentration was effective in preventing uropathogenic E. coli biofilm formation on urinary catheters. Further, the inhibitory effects were associated with a reduction in EPS production and gene expression of the bacteria. Additionally, at higher concentrations, selenium was effective in inactivating preformed bacterial biofilms on catheters within 3 days of incubation. These observations suggested that selenium could be potentially used in the control of bacterial biofilms on the catheters [ 86 ]. Also, it was shown that selenium-containing analogs of L-proline and L-cystine are effective in the treatment of UTI [ 87 ]. A study was conducted to compare the blood level of retinol and selenium in a person who suffered from minor lower urinary lesions. The results showed that there was a significant difference in the mean blood level of selenium between cases and control groups [ 88 ].

Copper, Cu, is an essential micronutrient for optimal innate immune function, and the nutritional deficiency of this element leads to increased susceptibility to bacterial infections [ 11 ]. During clinical UTI, uropathogenic E. coli upregulated the expression of copper efflux genes in patients. And, this element as a host effector could be involved in protection against pathogen colonization of the urinary tract [ 89 ]. Moreover, Cu export transport in bacteria has been addressed as an important virulence and fitness determinants during UTI [ 90 ]. Copper supplementation in drinking water has been suggested as an effective approach to reducing E. coli colonization in the urinary bladder of the animal model [ 91 ].

2.2.3 Other agents

Citrate salts could be used in the management of UTI due to their ability to alkalinize the urine, and alkaline urine is helpful for UTI symptoms such as dysuria. It was shown that by the administration of sodium citrate in women with UTI problems for 48 h, the symptoms were significantly improved in 80 percent of the subjects [ 92 ]. Additionally, alkalinity in the urine provides an effective environment for some of the antimicrobial agents such as uva-ursi and berberine to perform their function [ 37 ]. The role of these salts in the treatment of urinary candidiasis has been mentioned in an earlier study [ 93 ].

Simple sugars such as D-mannose could prevent the adherence of pathogens to uroepithelial cells. Various evidences show that the implementation of mannose exerts beneficial results in the treatment of UTI. It was shown that a mannose-specific lectin exists on the surface of adherent strains of E. coli and the sugar acts as the primary bladder cell receptor site for UPEC to bind [ 94 ]. Likewise, it was reported that in the adhesion of UPEC to the uroepithelial cells, the first step is the binding of FimH adhesin to the bladder epithelium through the interaction of mannose moieties with the host cell surface [ 95 ]. So, the use of the sugar or its analogs can help to block the adhesion of E. coli to the bladder epithelium. The efficacy of these sugars in controlling UTI has been studied previously [ 96 , 97 , 98 ].

An in vivo study indicated that demonstrated D-mannose in mice not only blocked adhesion of E. coli to the epithelium of the urinary tract but also prevent bacterial invasion and biofilm formation [ 99 ]. Also, in the presence of D-mannose, the adherence of clinical isolates of E. coli was inhibited remarkably [ 100 ]. Oral supplementation of D-mannose decreases the perception of lower urinary tract symptoms in postmenopausal women [ 101 ]. The results of another study indicated that D-mannose efficiently blocked the adhesive properties of all type 1 fimbriae-positive isolates of E. coli in low concentration, but did not show any bacteriostatic effects [ 102 ]. The results of another study demonstrated that antibiotic therapy in combination with long-term enrichment of the diet with D-mannose leads to prolongation of the inter-relapse period of uncomplicated UTI [ 97 ].

The effects of different derivatives of the sugar in the control of UTIs were studied. Klein et al. synthesized and evaluated the efficacy of these sugars in blocking bacterial-host interaction. Among them, para-substituted biphenyl derivative was the most effective agent in controlling UTIs. Following oral administration of this compound, bacterial numbers were reduced by twofold and fourfold in the urine and bladder, respectively [ 103 ].

2.3 Probiotics

Probiotics are living microorganisms which when administered in certain numbers exert a health benefit on the host [ 104 ]. The clinical efficacy of probiotics for adjunct treatment in the treatment of different gastrointestinal and urinary tract infections has been addressed previously [ 105 ]. They have demonstrated positive effects in the treatment and prevention of rotavirus diarrhea and alleviation of the antibiotic-associated intestinal adverse effects by recognizing the commensal microbiota and also restoration of the microbial ecosystem after an imbalance or infection [ 106 ]. Probiotics are clinically proven to be effective in the management of UTI including accelerating recovery after UTI and also decreasing recurrent UTI in children [ 107 ]. It must be emphasized that, for better effectiveness of probiotics, they must be able to colonize in the intestinal and/or urogenital region [ 108 ]. These positive effects of probiotics might be attributed to the intrinsic properties of microorganisms. For example, lactobacilli are able to grow in an environment with pH ≤ 4.5, where they could multiply and produce additional antibacterial molecules, such as bacteriocin and hydrogen peroxide [ 109 , 110 ]. Besides these advantages, probiotics could produce biosurfactants that inhibit the growth of uropathogens by reducing the adhesion of the pathogens to the uroepithelium. Moreover, lactobacilli could co-aggregate with uropathogens and block their adhesion to the urinary tract and also displace previously adherent uropathogens from uroepithelium. This process can create a microenvironment in which the inhibitory products of lactobacilli can concentrate on the pathogens and therefore inhibit the pathogens [ 111 ]. It is worth noting that the most effective lactobacilli for controlling UTI are L. rhamnosus GR-1 and L. reuteri B-54 and RC-14 which have been proven [ 108 ].

The common vaginal Lactobacillus species were used to investigate the inhibition of E. coli growth. The results showed that when L. crispatus was incubated with clinical E. coli strains, the growth of E. coli was inhibited in the acidic environment [ 112 ]. Wolff et al. studied the changes in the ratio between uropathogens and Lactobacillus (U/L) within the lower UTI in response to oral probiotic supplementation. Based on the results, there were no changes between groups in terms of microbiota diversity and the use of oral probiotic did not alter the U/L ratio [ 113 ]. The physicochemical cell surface, adhesion properties, and the antagonistic activity of recombinant Lactococcus lactis containing the Ama r 2 gene against the E. coli causing UTI in humans were studied. The results indicated that this recombinant probiotic showed desirable properties and the Ama r 2 gene expression did not affect the positive probiotic properties [ 114 ].

The ability of a clinically isolated probiotic, L. fermentum strain 4–17, to adhere to human intestinal was studied. L. fermentum strain 4–17 showed appropriate anti-adhesive properties against human pathogenic bacteria [ 115 ].

Osset et al. [ 116 ] studied the antimicrobial activities of 15 Lactobacillus species against pathogens. Among them, L. crispatus could block pathogen adhesion efficiently.

The results of another study revealed that a pyelonephritic E. coli was sensitive to L. rhamnosus , Bifidobacterium lactis, and Bifidobacterium longus and these probiotics were able to suppress the growth of enteric and urinary pathogens [ 117 ].

Oral administration of multispecies probiotic formulations showed antimicrobial activities against the pathogens that are responsible for vaginal dysbiosis and infections [ 118 ].

The effects of vaginal suppositories of probiotics for the prevention and treatment of UTI have been studied previously. The concept for instilling probiotic into the vagina might be related to the belief that by the presence of probiotic as the dominant bacterium the ascension of uropathogens into the bladder was restricted by various mechanisms, such as interfering with pathogen adhesion, biofilm formation reduction, reducing the expression of virulence factors, and also modulation of the host’s defense systems to better combat infection [ 108 ]. The Lactobacillus strains inhibited the growth of E. coli via the production of organic acids. Additionally, the adhesion and internalization of E. coli into HeLa cells were reduced by probiotics [ 119 ]. Reid et al. investigated the effect of probiotic lactobacilli in controlling acute UTI in women. Based on the results, recurrence reduced remarkably in the Lactobacillus group compared to the placebo group [ 120 ].

Taken together, the results of these aforementioned studies demonstrated the potential benefit of probiotics in controlling UTI.

Additionally, site-oriented probiotic therapy has been recognized as one of the most promising therapeutic alternatives for the prevention of UTI in post-antibiotic therapy [ 112 ].

While most clinical research showed using these natural substances represents a promising approach, further studies are needed to prove their mechanism of action and clinical effectiveness. It should be noted that formulating these substances in a single dosage form and their side effects and interactions with each other are the main limitations of developing a new formulation.

3 Conclusion

Treatment with non-antibiotic agents is a good approach to reduce the risk of incidence of UTI and also decrease the symptoms of the illness. Among these agents, natural substances, nutrients, and probiotics attract attention. Each of these agents acts by a different mechanism, and therefore, co-formulation of them in a single dosage form maybe provides the natural formulation that is effective for both preventive and therapeutic approaches in the management of UTI.

Availability of data and materials

This review was based on data extracted from published papers available in all relevant databases without limitation up to October 1, 2020.

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Bibi Sedigheh Fazly Bazzaz

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Fazly Bazzaz, B.S., Darvishi Fork, S., Ahmadi, R. et al. Deep insights into urinary tract infections and effective natural remedies. Afr J Urol 27 , 6 (2021). https://doi.org/10.1186/s12301-020-00111-z

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Definitions of Urinary Tract Infection in Current Research: A Systematic Review

Affiliations.

• 1 Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
• 2 Center for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
• 3 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
• 4 Department of Internal Medicine, Haga Teaching Hospital, The Hague, The Netherlands.
• 5 Health Campus The Hague, Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
• 6 Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
• 7 Geriatrics Research Education and Clinical Center, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA.
• 8 Department of Emergency Medicine, The Ohio State University, Columbus, Ohio, USA.
• 9 Amsterdam University Medical Center, Department of Internal Medicine, Amsterdam Institute for Infection and Immunity, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
• 10 Department of Urology, University of Szeged, Szeged, Hungary.
• 11 Clinic for Urology, Paediatric Urology and Andrology, Justus Liebig University, Giessen, Germany.
• 12 Medical Research Council Unit for Lifelong Health and Ageing, University College London, London, United Kingdom.
• PMID: 37426954
• PMCID: PMC10323732
• DOI: 10.1093/ofid/ofad332

Defining urinary tract infection (UTI) is complex, as numerous clinical and diagnostic parameters are involved. In this systematic review, we aimed to gain insight into how UTI is defined across current studies. We included 47 studies, published between January 2019 and May 2022, investigating therapeutic or prophylactic interventions in adult patients with UTI. Signs and symptoms, pyuria, and a positive urine culture were required in 85%, 28%, and 55% of study definitions, respectively. Five studies (11%) required all 3 categories for the diagnosis of UTI. Thresholds for significant bacteriuria varied from 10 3 to 10 5 colony-forming units/mL. None of the 12 studies including acute cystitis and 2 of 12 (17%) defining acute pyelonephritis used identical definitions. Complicated UTI was defined by both host factors and systemic involvement in 9 of 14 (64%) studies. In conclusion, UTI definitions are heterogeneous across recent studies, highlighting the need for a consensus-based, research reference standard for UTI.

Keywords: complicated urinary tract infection; cystitis; definition; pyelonephritis; urinary tract infection.

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

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Conflict of interest statement

Potential conflicts of interest. All authors: No reported conflicts.

Preferred Reporting Items for Systematic…

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of the study…

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Prevalence of Urinary Tract Infection Among Pregnant Women and its Complications in Their Newborns During the Birth in the Hospitals of Dezful City, Iran, 2012 - 2013

Marziyeh amiri.

1 Student Research Committee, Dezful University of Medical Sciences, Dezful, IR Iran

Zohreh Lavasani

2 Department of Obstetrics and Gynecology, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, IR Iran

Reza Norouzirad

3 Department of Biochemistry, Dezful University of Medical Sciences, Dezful, IR Iran

Reza Najibpour

4 Student Research Committee, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, IR Iran

Masoomeh Mohamadpour

5 Department of Anatomy, Histomorphometry and Stereology Research Centre, Shiraz University of Medical Sciences, Shiraz, IR Iran

Amin Reza Nikpoor

6 Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

Mohammad Raeisi

7 Department of Immunology, Shiraz University of Medical Sciences, Shiraz, IR Iran

Hadi Zare Marzouni

Background:.

Urinary tract infection (UTI) is the most common disorder caused by bacterial agents in pregnancy, which can lead to important complications in newborn of such mothers in case of inappropriate diagnosis and treatment.

Objectives:

The purpose of this study was to study the prevalence of UTI among pregnant women and its complications in their newborns during the birth in the hospitals of Dezful City, Iran, during 2012 - 2013.

Patients and Methods:

In this cross-sectional retrospective study, 1132 women admitted to Dr. Ganjavian and Ayatollah Nabavi Hospitals in Dezful City, Iran, during 2012 - 2013 were randomly allocated into the case and control groups and were matched based on their age, numbers of pregnancy, sex and diseases of their children. UTI was the only difference between the two groups.

Twenty-two thousand six hundred deliveries occurred within the course of this study. Due to UTI, 5% of deliveries led to hospitalization of mothers (1132 patients).Weight and height of newborn infants of mothers afflicted with UTI (P < 0.001) were significantly lower compared to newborns of healthy women (P < 0.001). There was a significant association between the two groups of pregnant women with UTI in terms of type of delivery (normal and caesarean section) (P < 0.008).

Conclusions:

The lower incidence of UTI in pregnant women compared to other areas of Iran represents the role of climate and weather in the prevalence of UTI. In addition, the increased number of low-birth-weight infants had a remarkable correlation with UTI, which can influence the health of the next generation.

1. Background

Various microorganisms are able to invade the urinary tract and can be involved in the pathogenesis of urinary tract infection (UTI) ( 1 - 4 ). As one of the most common recurrent acquired infections, UTI has a conspicuous role in increasing the number of stillbirth deliveries ( 5 - 7 ).

Urinary tract infection and its associated complications are the cause of nearly 150 million deaths per year worldwide. The disease can be developed in 40% - 50% of women and 5% of men ( 8 ). After anemia, UTIs are the second common complications in pregnant women, which if not controlled well, can adversely affect the health of infant or the pregnant mother ( 9 , 10 ). Pregnancy UTI is classified into two categories of symptomatic and asymptomatic ( 11 , 12 ): A) The involvement of the lower urinary tract, leading to asymptomatic bacteriuria is the most common cause of UTI during pregnancy. B) The involvement of the upper urinary tract can lead to symptomatic bacteriuria and is characterized by acute Pyelonephritis ( 13 ). Based on performed researches, the prevalence of symptomatic urinary tract infection in pregnant women has been 17.9% and asymptomatic form in 13%. If asymptomatic infection is not treated, it leads to some clinical manifestations in mother and newborn ( 12 , 14 ).

Increased age, number of childbirths, number of intercourses per week, diabetes, recessive sickle cell anemia, previous history of UTI, immunodeficiency and urinary tract abnormalities can increase the risk of UTI in pregnant women (15, 16). Bacterial organisms, which cause this disease, include Escherichia coli , Klebsiella pneumonia , Proteus , Acinetobacter , Saprophyticus Staphylococcus , Streptococcus Group B and Pseudomonas aeruginosa ( 13 , 15 - 17 ). The incidence of UTI increases by pregnancy. Based on pervious researches, the probability of UTI initiated by the sixth week. This probability peaks at 22 - 24 weeks of gestational age. The reasons for increased probability of infection in pregnant women are probably increased bladder volume and its expansion and expanded ureter ( 15 , 18 ). Anatomical and physiological changes occurring during pregnancy alter the course of bacteriuria and make pregnant women more susceptible to UTI complications such as pyelonephritis ( 19 ).

Studies have indicated that 25% - 40% of untreated pregnant women with asymptomatic bacteriuria will eventually develop to acute pyelonephritis as the most common cause of predelivery hospitalization ( 19 ). Furthermore, even if pyelonephritis is treated immediately, the condition significantly increases mortality and the number of infants with low-birth weights. In addition, anemia, preeclampsia and premature rupture of fetal membranes, respiratory failure and risk of septicemia and shock are other risk factors in UTI pregnancy. Moreover, children born with mothers with pyelonephritis are much more prone to impairment of mental and motor development ( 3 ). There is a significant statistical correlation between UTI and congenital retardation ( 20 ). In addition, according to some studies, UTIs are associated with premature delivery, low-birth-weight infants, cesarean delivery, morphological abnormalities and infant mortality ( 13 , 21 , 22 ). It should be noted that according to the studies, UTI in pregnant women begins in the 6 th week of pregnancy and reaches its peak in weeks 22 - 24 and about 90% of these women develop urethral dilation. In pregnant women, due to an increase in the volume of urine and dilation of urethra, the disease causes increased stasis of urine in the bladder, reflux of the urine to the urethra and causes a physiological increase in plasma volume, which will eventually reduce the urinary concentration. Another common reason is glycosuria, which is present in 70% of pregnant women, increases the urinary level of estrogen and progesterone, and decreases the patient’s ability to fight invasive bacteria. All these factors may contribute to the development of UTI in pregnancy ( 13 , 23 ). In the recent studies, different reasons were mentioned for this disorder in pregnancy. The commonest microbial agent for this disease has been E. coli resistant species, which needs special attention ( 24 , 25 ).

2. Objectives

Considering the importance of UTI in pregnant women which is responsible for several complications, its diagnosis and treatment are essential to maintain the health of mother and baby. Therefore, the purpose of this study was to examine the prevalence of UTI among pregnant women and its complications in their newborns during the birth in the hospitals of Dezful city during 2012 - 2013.

3. Patients and Methods

In this cross-sectional retrospective study, 1132 women admitted to Dr. Ganjavian and Ayatollah Nabavi hospitals in Dezful city, Iran, during 2012 - 2013 were randomly allocated into case and control groups and their medical records were studied. This study was conducted after the approval of the ethics committee of the University. In this study, the inclusion criteria for pregnant women during the 20 th - 26 th weeks of pregnancy in the case group was the positive urine cultures of bacteria (more than 105 colonies growth in a standard positive urine culture) as well as more than 12 × 10 9 /liter leukocytes in their blood sample ( 23 , 25 , 26 ). Also, the inclusion criteria for the pregnant women during the 20 th - 26 th weeks of pregnancy in the control group was the negative urine culture and the presence of normal levels of leukocytes (4.4 - 11.3 × 10 9 L). These tests were conducted in the bacteriology and hematology departments of the central laboratory of Dr. Ganjavian and Ayatollah Nabavi hospitals in Dezful city and they have been confirmed.

The number of pregnant women hospitalized during the 20 th - 26 th weeks of their pregnancy due to the treatment of UTIs was determined after studying. The records of all pregnant women of this city were studied during 2011 - 2012.Then parameters such as type of delivery, cause of UTI and infants' height and weight at birth were studied from their medical record and the frequency of each parameter was specified. To compare the complications and impact of UTI on the factors measured in this study, two groups of case and control were chosen and studied.

The study group (case group) consisted of all the pregnant women referred to and hospitalized in one of the two hospitals of Dezful city due to UTI during the 20 th to 26 th weeks of their pregnancy between 2012 and 2013 and the control group consisted of the same number of pregnant women who did not have UTIs during the 20 th - 26 th week of their pregnancy and referred to one of the two hospitals of Dezful city to give birth during 2012 - 2013.Selection of subjects among eligible population in the case group was through census and was through simple random sampling in the control group. In addition, the two groups were reviewed and matched in terms of age, number of pregnancies, underlying disease in the mother and the gender of the infant. Weight below 2500 g was considered lower than normal ( 25 ). In this study, existing software was used to analyze data. In the descriptive statistics, average indices and absolute and relative frequency and in the inferential statistics, to test the relationship between the variables, independent-sample test and chi-square test were used. P value < 0.05 was considered as statistically significant. The ethics committee of Dezful university of medical sciences approved the study protocol. The code of ethical approval is DURs100.

Based on the results obtained during 2012-2013, 22600 women have given birth in the hospitals of Dezful city (15200 women in Dr. Ganjavian hospital and 7400 women in Ayatollah Nabavi hospital) and 5% of them (1132 women) were hospitalized due to UTI and they had medical records in both archive department and registration office in the central laboratory of Dr. Ganjavian and Ayatollh Nabavi hospitals. The achieved results showed that 812 of 1132 women with UTI were hospitalized in Dr. Ganjavian Hospital and 320 women in Ayatollah Nabavi Hospital. The prevalence of UTI among pregnant women was different based on the hospital and the time of admission. Furthermore, 462 cases (56.8%) from 812 women admitted to Dr. Ganjavian hospital were infected during the year 2012 whereas there was a decline in the number of infected women in 2013 which was 350 (43.1%). There was no significant difference in the number of infected women between the two years of admission (P < 0.001). From a total of 320 women, 115 (35.9%) and 205 (64%) cases were admitted to Ayatollah Nabavi Hospital in the years of 2012 and 2013, respectively. There was no significant difference in the number of infected women between the two years of admission (P < 0.001).

The mean age of women with UTI in this city was 27.32 ± 1.26 years and the maximum age group with UTI was in the range over 30 years (5.91%) and the minimum age group ranged from 25-30 years (4.64%). As shown in Table 1 , the highest rate of UTIs in terms of the type of delivery was in the women with the second type (6.49%) (P < 0.001). The highest rates of UTIs among pregnant women of this city were in the winter (55.12%) and the lowest rates were in the summer (8.3%) (P < 0.001) ( Table 2 ). The city has the highest rate of UTI in pregnant women (57.25%), due to the presence of E. coli (P < 0.001). Bacterial agents causing UTI in pregnant women were different in number and percentage. Escherichia coli and Klebsiella species with the total number of 648 (57.25%) and 236 (20.85%) were found as the most frequent types of bacteria, respectively. The frequency rates of Coagulase-negative staphylococci , Streptococus species, Acinetobacter , Proteus Mirabilis , Staphyloccus aureus , Enterobacter aerogenes were 95 (8.39%), 75 (6.63%), 28 (2.47%), 27 (2.38%), 19 (1.68%) and 4 cases (0.35%), respectively. The rate of cesarean section in pregnant women with UTI was 47.96% (543 women) (P < 0.001). The major reason resulting in performing cesarean section was Klebsiella bacteria and 72% of the cases infected with klebsiella were undergone cesarean section (P < 0.001). Escherichia coli rates after Klebsiella accounted for 48.3% of the cases (Its frequency is expressed in Table 3 with resolution).

a Abbreviation: UTI, urinary tract infection.

b All data are presented as No. (%).

a P. value (Chi-square) is < 0.0001.

b P. value (Chi-square) is 0.189.

c All data are presented as No. (%).

a P value is < 0.001.

b All values are presented No. (%).

In this study, in order to compare the complications and effects of UTIs, 2264 pregnant women participated and 1132 of them had UTI with positive culture (in the case group) and 1132 of them had negative urine culture (in the control group). By describing the data collected in this study, findings indicated that there was no significant difference between the two groups (the case and control) in terms of demographic variables ( Table 4 shows the frequency of demographic characteristics between the two groups.). The average number of pregnancies was 1.79 in the case group and 1.94 in the control group.

a All values are presented as No. (%).

The average weight of the infants at birth was 3169.16 g in newborns with healthy mothers and 2886.66 g in newborns of mothers with UTI (P < 0.001). The highest and the lowest weights of the infants in the case group were 4750 g and 750 g, respectively and for the infants in the control group were 5100 and 900 g, respectively. Weights of the infants of mothers with UTI were significantly lower than the weights of the infants with healthy mothers (P < 0.001) and 43.28% of the children in the case group have weights below normal (2500 grams) and their frequency is shown in Table 5 .

a P < 0.001.

There was a significant relationship between the two groups of pregnant women in terms of types of delivery (normal and cesarean section) (P = 0.008); so that the rate of cesarean section in women with UTI (the case group) is reduced to 47.96% and in women without UTI (the control group) to 31.71% (359 women).Their frequency is expressed in Table 6 . The highest rates of cesarean delivery in both case and control groups were (60.97%) and (53.22%), respectively.It has been in the range of 25 - 30 years of age and in the second pregnancy ( Table 7 shows their frequency). As depicted in Table 8 , the average height of these infants in the case group was 48.52 cm which was 2.46 cm shorter than the heights of the infants of healthy mothers (P < 0.001).

a P value is 0.008.

b All values are presented as No. (%).

b P < 0.0001.

c P value is 0.0204.

5. Discussion

This study investigated the incidence of UTI in pregnant women and its impact on the health and growth of their infants for the first time in the Dezful city, Iran. The results of our study showed that 5% of the pregnant women of this city were infected with UTIs during their pregnancy between 2012 and 2013 and were hospitalized in Dr. Ganjavian and Ayatollah Nabavi Hospitals due to UTI. The incidence of UTI was 12.3% in a study done by Soleymanizadeh et al. on 1500 pregnant women in the city of Bam ( 27 ). In another study conducted by Mobbasheri et al. on 900 pregnant women in the city of Gorgan, the incidence of UTI was 3.7% among them ( 28 ). In addition, in studies conducted in different regions of the world, Bookallil et al. study in Australia ( 29 ), Turpin study in Ghana ( 30 ), Hernandez study in Mexico ( 31 ), and Tadesse in North West Ethiopia ( 32 ) can be pointed out which results indicated UTI of 4.9%, 7.3%, 8.4%, 9.8% in those areas, respectively. Thus, according to the findings of this study, the prevalence of UTI in this city is lower than other areas and according to statistics of the incidence of UTI in different seasons of the year and a dramatic reduction of the infection in summer, this lower prevalence of UTI in Dezful city may be due to climate conditions and hot weather of this city. Decreased incidence of UTI may also be a result of the subject selection method, treatment in other medical centers, selecting subjects with symptomatic UTI and cultural and social characteristics of each society. Generally, studies insist on the fact that UTI is one of the most important infectious diseases in Iran, which needs further attention ( 2 ).

Based on the results of this research, the highest rate of UTI among pregnant women in Dezful is in the ages over than 30 and the lowest rate of infection is between the age range of of 25 - 30 years. In a study by Mobbasheri et al. in Gorgan, the highest age of infection in pregnant women has been in the age group over 35 years (8.4%) ( 28 ). In a study carried out by Al-Haddad AM in Yemen, the highest rate of infection (53.7%) in pregnant women was in the age range of 15 - 24 years ( 7 ).

According to the results of this study, the highest incidence of UTI among pregnant women of this city depending on the rank of the delivery was in the second pregnancy and the lowest rate of infections was after the third pregnancies; however, in a study conducted by Mobbasheri and et al. in Gorgan, the highest rate of infections was after the third pregnancies (4.73%) ( 28 ). The results from the studies of Mobbasheri et al. were consistent with the results from the study of Gibb et al. in America ( 33 ). Based on the results of this study, lowest rate of infections in pregnant women of this city was in summer and the highest rate of infection was in winter, which can demonstrate the effects of temperature on the incidence of UTI. The results from the study that John E Anderson did in Canada represents the fact that seasonal change is of the main factors affecting UTIs in women. Based on this study, it is reported that UTIs occur more in summer (the third quarter of the year) rather that in winter ( 34 ). Moreover, in a retrospective study done by Elo et al. during the years 1965 - 1974 in Finland, it was demonstrated that the highest rate of UTIs were in November (winter) and the lowest rate of it were during the summer season. In addition in this study, the results from the analysis of climate conditions showed that unconventional climate such as cold and dry weather in autumn and warm and dry weather in spring is associated with obvious changes in the number of UTIs ( 35 ).

Findings of the present study demonstrated E. coli as the main cause of UTIs in pregnant women of this city (57.25%) and Klebsiella as the second cause of UTI (25.85%). In a study conducted by Amiri et al. in Babol city, E. coli was indicated to be the cause of 83% of UTIs in pregnant women and staphylococcus saprophyticus (10%), enterococcus (4%) and proteus (3%) were other causes of UTIs ( 36 ). Also, the results from the studies of Mobbasheri et al. in Gorgan mark that E.coli 33.3 % coagulase negative staph 30.3% and klebsiella 15.2% are the major causes of UTIs among pregnant women ( 28 ). The results from the study of Emamghorashi in Jahrom ( 13 ) also indicate the major role of E. coli in UTIs among pregnant women of those regions, which included more than 50% of all cases. Moreover, in studies conducted by Masinde in Tanzania ( 5 ), Al-Haddad in Yemen ( 7 ), Hamdan in Sudan ( 37 ) and Totsika in Australlia ( 8 ), E. coli was the main cause of UTIs among women of those areas and the prevalence in those regions were 47.2%, 41.5%, 42.4%, respectively. These studies show that UTI caused by E. coli is more prevalent in Iran than other studied areas.

Based on the results of the present study, cesarean rate was 48.33% in the case group and 31.33% in the control group and a significant difference was seen between the rate of infection and type of delivery. In the study of Fathian et al. in Isfahan, cesarean rate was 52.4% in pregnant women. In this study performed during the second half of the year 2000, which was titled monitoring and evaluation of reproductive birth project, cesarean rate was 42.3% during this time nationwide. Also, according to world health organization (WHO) in 2010, only 10% to 15% of C-section cases were justified due to medical reasons ( 38 ); therefore, we conclude that in addition to the fact that rate of cesarean deliveries in the country is much higher than the WHO’s standards, UTI is one of the main reasons causing cesarean deliveries and it has a direct correlation with C-section.

According to this study, the average weight of newborns whose mothers had UTI was 2886.66 gr and it was 282.5 gr lower than the newborns of healthy mothers. Furthermore, 43.33% of the infants in the case group have weight lower than normal. In the study of Emamghorashi and et al. in Jahrom, 21% of newborns whose mothers had UTI had weights lower than normal. Also, 11% of mothers under study with UTI had stillbirth ( 13 ). So, based on the results of this study and other similar studies, it can be concluded that UTI in pregnant women has an adverse effect on their babies. Moreover, the results from the recent studies have been shown that treatment of UTI may be of considerable importance not only to forestall complications in the mother, but also to reduce prematurity and fetal mortality in the offspring.

In conclusion, one of the main limitations in the present study was the incomplete data of some of the patients, which lead to exclude them from the study. Also, we may miss some of the pregnant women with UTI, who admitted to our studied hospitals for their delivery, but admitted to other medical centers for treatment of UTI.

The results of the present study indicate a 5% prevalence of UTI in pregnant women in Dezful City and also show a significant correlation and the direct impact of this disease on the weight, growth and health of their infants at birth. In addition, according to the conducted studies, UTI in mothers is the major reason for low-birth-weight infants. It seems that policy makers and health planners of Dezful city can have a major role in reducing the risk of infection and complications in pregnant women by creating awareness regarding the causes and symptoms of UTI and prevention of the factors causing it especially with educating women before and during pregnancy.

Acknowledgments

We would like to extend our thanks to the staff of Dr. Ganjaviyan and Ayatollah Nabavi Hospitals. We appreciate the research deputy of Dezful University of Medical Sciences for providing the financial support. The authors have no conflicts of interest in this article.

Authors’ Contributions: Marziyeh Amiri: Acquisition of data, implementation of the study, manuscript preparation, study conception, contributions to principal investigation, and critical revision of the manuscript, study supervision Zohreh Lavasani: manuscript preparation, revision of the manuscript for important intellectual content. Reza Norouzirad: Contributions to conceive the study, principal investigation, critical. Amin Reza Nikpoor: manuscript preparation, revision of the manuscript for important intellectual content, statistical analysis. Hadi Zare Marzouni: Contributions to conceive the study, analysis and interpretation of data, and statistical analysis. Masoomeh Mohamadpour: principal investigation, revision of the manuscript for important intellectual content. Mohammad Raeisi: principal investigation, revision of the manuscript for important intellectual content Najibpour reza: Contributions to conceive the study, and submit the article.

Financial Disclosure: Authors have no relevant financial interests within the past 5 years and for the foreseeable future.

Funding/Support: This study was supported in part by research deputy of Dezful University of Medical Sciences (grant no: DURs100).