The Diagnosis, Treatment, and Prevention of Recurrent Urinary Tract Infection

Background: Urinary tract infection has a one-year prevalence of 11% in women and ranges among the most common reasons for consulting a primary care physician and for receiving a prescription for antibiotics. In the case of recurrent urinary tract infection (rUTI), there are questions about the further work-up, treatment, and preventive measures.

Methods: The systematic literature search performed for the update of the German clinical practice guideline on uncomplicated urinary tract infection (043–044) (up to February 2022) was supplemented with a selective search for clinical trials (up to August 2023).

Results: Urine culture and ultrasonography are reasonable steps in the diagnostic evaluation of rUTI. Further invasive testing is suggested for men but is not routinely indicated for women. Antibiotics are among the most effective preventive measures (risk ratio [RR] 0.15, 95% confidence interval [0.1; 0.3]) but carry a high risk of side effects. Non-antibiotic preparations such as cranberry juice (RR 0.74 [0.5; 0.99]), mannose (RR 0.23 [0.14; 0.37]), and vaginal estrogen (RR, 0.42 [0.30; 0.59]) can also reduce the infection rate, with a low risk of side effects. Increased daily fluid intake has been shown to lower infection rates in the short term (odds ratio [OR] 0.13 [0.07; 0.25]); the use of hygienically advisable wiping techniques after passing stool or urine has been little studied but can be implemented with no risk.

Conclusion: rUTI poses a challenge for the treating physician. The measures to be taken must be considered on an individual basis. Vulnerable groups, such as older patients, need special attention.

All urinary tract infections produce symptoms that impair the quality of life (1). The infection is usually limited to the urinary bladder (2), with pyelonephritis making up only about 1% of all urinary tract infections (3). Frequently recurring urinary tract infections are considerably harder to manage and must be treated on an individual basis. Recurrent urinary tract infections (rUTI) lead to frequent antibiotic treatment, which, in turn, is largely responsible for the selection pressure on the causative pathogens. In this review, we present the current state of knowledge on the causes and treatment strategies in different groups of patients with rUTI, focusing on infections of the lower urinary tract.

Learning objectives

This article should enable the reader to:

• know the risk factors for the development of recurrent urinary tract infections,
• categorize and evaluate the use of different diagnostic procedures for the further work-up of recurrent urinary tract infections (rUTI), and
• know the antibiotic and non-antibiotic preventive treatment approaches and be able to implement them in routine clinical practice.

Methods

Pertinent publications up to February 2022 (4) were retrieved by a systematic literature search carried out for the update of the S3 guideline on uncomplicated urinary tract infections (43, 44). A further selective search for clinical studies published thereafter (up to 17 August 2023) was carried out in PubMed and Cochrane. The filters used for the PubMed search were “therapy” and “diagnosis.” This review is based on the systematic reviews and meta-analyses identified in these literature searches and on the synopsis of the guideline. Recent randomized and controlled clinical trials (RCTs) were included as well.

Frequency and Definition

With an annual prevalence of 11% among women over age 16, urinary tract infection is among the more common reasons for consulting a primary care physician (5). They are the second most common reason for an antibiotic prescription after respiratory infections (6). Women suffer from UTIs much more commonly than men, and prevalence increases with age (3).

Various diagnostic and therapeutic considerations have made it useful to distinguish between uncomplicated and complicated urinary tract infections. An uncomplicated UTI is one without any relevant functional or anatomical abnormality in the urinary tract, any relevant renal dysfunction, or any relevant prior or current conditions that predispose to UTI or severe complications of UTI.

A UTI increases the risk of a later UTI. Recurrent UTI (rUTI) is defined as at least three infections in a single year, or at least two in the past six months (2).

A new UTI after a prior UTI may represent either a relapse or a new infection. Relapses are caused by persistence of the pathogen despite initially successful treatment; they occur within 14 days, by definition (7). There is no consensus on whether a UTI relapse should be counted in the diagnostic criteria for rUTI.

In what follows, we discuss the diagnostic evaluation and treatment of this condition and management strategies for it, with separate consideration of male and female patients and of geriatric patients. The latter are defined as frail older women and men with more than two systemic diseases requiring treatment (8). The definition includes those who are still cared for at home as well as those living in old age and nursing homes (8).

Epidemiology

In a representative survey of the British population, 2424 women aged 16 and above were asked about the frequency and (self-)treatment of UTIs (5). 37% reported having had at least one UTI in their lifetime; among these women, 79% reported multiple infections. 11% said they had had an infection in the past 12 months, and 3% reported recurrent infections (at least 3) in the past 12 months. An analysis of routine data from a German health insurance company (3) revealed an 8.2% annual prevalence of UTI among all insured women in 2019 (corresponding figure for men, 2.1%). Routine data are unsuitable for determining the frequency of recurrent UTI for methodological reasons.

Nonetheless, information on the frequency of rUTI in women with acute UTIs can be found in published descriptions of included subjects in clinical trials. rUTI frequencies ranging from 8% to 20% (8, 9) over 6 or 12 months have been reported in studies from various countries.

The prevalence of UTI rises with age in men as it does in women, and one may thus expect the prevalence of rUTI to rise in men as well. In an American cohort study of men (average age 67.9 years), just under 10% of the men (average age 67.9 years) who had a UTI had another UTI within a year. Almost 2% of the men with UTI met the defining criteria for rUTI (9).

A retrospective analysis of urine cultures in Germany yielded similar findings. The prevalence of rUTI among men rose markedly with age and was highest in men over 70 (10).

Data on the prevalence of rHWI in a geriatric population are subject to marked diagnostic uncertainty. Reasons are the frequent absence or atypical nature of clinical signs of UTI in this group and the age-related rise in asymptomatic bacteriuria (ABU), because of which a positive urine test strip cannot be regarded as definitive evidence of a UTI (11). UTI is thus often overdiagnosed and overtreated in the geriatric population (12). In a British retrospective cohort study, 2.7% met the diagnostic criteria for RUTI (13).

Pathogens causing urinary tract infections

By far the most common pathogen causing UTIs in women is Escherichia coli (E. coli). It is identified in around 74% of urine tests for uncomplicated infections (14, 15). Other common pathogens are Klebsiella pneumoniae and enterococci (5% each), Proteus mirabilis (5%), and Staphylococcus saprophyticus (2%) (14, 15).

The resistance situation in regard of the antibiotics that are recommended for the treatment of uncomplicated UTIs in women (fosfomycin, nitrofurantoin, nitroxolin, pivmecillinam, trimethoprim, Tables 1 and 2) is generally favorable: the rate of resistance to each of these drugs is well below 20% (14). As expected, resistance rates to organisms causing rUTI are higher: the reported resistance rates to trimethoprim, for example, are 14.5% in uncomplicated UTI and 24% in recurrent UTI (15).

Table 1

Percentages of resistance to antibiotics recommended for the empiric treatment of uncomplicated urinary tract infection due to uropathogenic organisms (14)

Table 2

Antibiotics recommended for the treatment of uncomplicated urinary tract infection*

E. coli is also the most frequently identified pathogen in men (38%), followed by enterococci (16%), Proteus mirabilis (9%), and Klebsiella pneumoniae (8%) (10). Data on the resistance of E. coli to the antibiotics nitrofurantoin (2%) or pivmecillinam (8%), which are primarily recommended for uncomplicated UTIs in men, are highly favorable as well, especially with regard to fluoroquinolones, which are used to treat complicated infections (20% resistance to ciprofloxacin). If antibiotics are prescribed without prior resistance testing, sensitivity rates are highest for nitrofurantoin (75%) and ciprofloxacin (78%) (10).

If the urine culture reveals mixed flora, potential contamination or errors in the pre-analysis stage should be considered. It may be useful to repeat the urine culture, with antibiotic treatment initially directed against the typical pathogen that had the highest bacterial count in the first culture.

The significance of a positive culture for enterococci in UTI is unclear; they are usually regarded as a contaminant. In all patients with rUTI, including geriatric patients, antibiotics that are used for the first-line treatment of uncomplicated UTI (Table 2) can still be given empirically, even though resistance to all antibiotics is now on the rise.

Risk factors for recurrent urinary tract infection

Aside from age and sex, risk factors for UTI and rUTI include systemic diseases (e.g., diabetes mellitus (odds ratio [OR] 1.5 [1.3; 1.7]) [16], immunodeficiency), relevant anatomical or functional abnormalities (e.g., vesicoureteral reflux, bladder dysfunction) and sexual activity (OR 1.4 [1.1; 1.9]) (17, 18). Some risk factors have only been identified in certain patient groups or are only present in these groups (Box 1).

Box 1

Typical risk factors for urinary tract infection in certain patient groups

Further diagnostic testing

rUTI is defined solely on the basis of the temporal pattern of reappearing disease, with no change in the diagnostic criteria for a UTI as such. Recurrent infections are usually caused by pathogens originating in the intestinal or vaginal flora.

Recurrent UTIs are associated with increased suffering (1). Patients and those who treat them desire not only effective treatment, but also, ideally, a pathophysiological explanation of why the infection recurred, as a guide to the prevention of further episodes. In clinical practice, the question regularly arises whether further diagnostic testing should be performed in order to identify a possible underlying condition.

There is no standard approach to the selection of further diagnostic tests or the circumstances in which they should be performed. In the current update of the S3 guideline issued by the Association of the Scientific Medical Societies in Germany (AWMF) (2, 4), abdominal ultrasonography is recommended in addition to urine culture in women with rUTI. Invasive testing, e.g., by cystoscopy, is not recommended, as relevant findings are only rarely detected by routine cystoscopy: in a systematic review, cancer was detected in only one of 656 cystoscopies in women with rUTI (21). In contrast, a further urological work-up is generally suggested for men with rUTI. This is mainly because the evidence regarding optimal treatment is still very limited, and because there is concern that relevant causes of uncertain prevalence (e.g., chronic bacterial prostatitis) might otherwise be overlooked. There are no standardized recommendations regarding the tests to be carried out.

Diagnosing a UTI is much harder in geriatric patients, as the symptoms are often nonspecific, and ABU is common (22). Algorithms that include a weighting of specific and non-specific symptoms and findings in this age group may be helpful (23). The mean frequency of ABU in nursing home residents is approximately 40% and rises above 70% in the presence of both urinary incontinence and dementia (24). The prevalence of ABU is much lower in men than in women. Among patients with an indwelling urinary tract catheter, the rate is already 100% after approximately 30 days (7). To date, there are no standardized recommendations for further diagnostic studies in elderly/geriatric patients; the treatment of concomitant diseases is generally determinative (e.g., treatment of urinary incontinence or bladder outlet obstruction, or adjustment of medication). Regular re-evaluation of the need for a urinary bladder catheter and consideration of possible alternatives are recommended in all of the current European guidelines (4, 7, 25). According to a meta-analysis, the type of catheter (coated versus uncoated) has no significant influence on the frequency of re-infection (risk ratio [RR] 0.87 [0.75; 1.00], p = 0.06) (26). In a prospective observational study, the frequency of newly occurring UTIs was significantly lower in patients with suprapubic, rather than transurethral, catheters (27). Whatever type of catheter is used, it is recommended to take a urine culture from a newly inserted catheter beforehand in the event of a suspected infection (4, 25).

Treatment options for recurrent urinary tract infection

There are a number of therapeutic approaches that share the goal of lowering the recurrence rate (Box 2).

Box 2

Treatment options for lowering the recurrence rate of urinary tract infection

The recommended behavioral changes and patient education relate to fluid intake, mode of contraception, and genital hygiene. The effect of such measures has been studied almost exclusively in women; our literature search did not reveal any clinical trials on the prevention of UTI in men with rUTI. According to a meta-analysis, increasing the daily fluid intake (by 200 to 2000 mL, depending on the trial) significantly lowers the infection rate (OR 0.13 [0.07; 0.25], p < 0.001) over the short term (< 6 months), but the effect is no longer seen at 12 months (with continuation of the increased fluid intake). The rate of antibiotic prescriptions was the same in the two groups (28, 29). Despite this small effect, increasing the fluid intake can be recommended to patients, as it reinforces their self-care and is very unlikely to be harmful.

The degree to which altered behavior lowers the frequency of infection is unclear, as no relevant randomized trials have been conducted. According to case-control studies, infection rates are lower when patients follow recommendations to wipe from front to back after using the toilet and to avoid postponing micturition or defecation (30, 31). The same holds for recommendations to urinate after sexual intercourse (30, 31) and not to clean the genitals after micturition (31), as doing so makes infections more common, presumably by damaging the protective vaginal flora. There is only low-level evidence for the benefit of these behavioral changes, but they can be recommended nonetheless, as there is little risk of harm and self-care is reinforced.

The use of spermicides increases the risk of UTI (perhaps by altering the vaginal flora), and switching to another contraceptive method may lower the frequency of recurrence. Botanicals play a large role in self-medication; many different preparations are said to be beneficial for the treatment and prophylaxis of UTIs. According to an HTA report commissioned by the IQWIG (32), cranberry preparations lower the recurrence rate compared to placebo.

The effect of cranberry preparations is thought to be due to inhibition of E. coli adhesion to urothelial cells by the proanthocyanidins that these preparations contain.

This positive assessment is further supported by a Cochrane Review (33) and a meta-analysis (34) showing a 30% reduction in the UTI recurrence rate by treatment with cranberry preparations (RR 0.70 [0.6; –0.8]; p < 0.01). A limitation to this conclusion comes from the use of different dosages, at different frequencies, in the practical implementation. A subgroup analysis suggested that cranberry juice is more effective than cranberry preparations in the form of capsules or tablets.

A further systematic review on phytotherapy in adults with rUTI (35) showed a benefit from tablets containing Seidlitzia (also called Soda) rosmarinus, a type of saltwort. This preparation is not available in Germany.

Local estrogenization

The risk of UTI increases in women after the menopause. It is thought that falling estrogen levels lead to a rise in vaginal pH, which, in turn, impairs protective colonization with Lactobacillus sp. According to a meta-analysis, local estrogen treatment (in contrast to oral substitution) can lower the rate of rUTI (RR 0.42 [0.30; 0.59]) (36). The maximum duration of treatment in the included studies was 36 weeks; in the absence of comparative studies, no conclusions can be drawn about the optimal duration of treatment or mode of application. In practice, the vaginal administration of 0.5 mg estriol 2–3 times per week is recommended.

Mannose

Mannose is a sugar related to glucose that is said to prevent UTI by impairing the adhesion of E. coli to urothelial cells. A Cochrane Review from 2022 reached no firm conclusion on the benefit of mannose for the treatment or prevention of UTI (37). A key reason for the assessment was the lack of adequate RCTs. According to a study published in April 2024, the rate of rUTI in pre- and postmenopausal women was not significantly lowered by the daily consumption of 2 g of mannose (RR 0.92 [0.80; 1.05]; p = 0.22) (38). Mannose is still a “can be offered” option in the German guideline on uncomplicated UTI; the Scottish guideline (7) contains a similar assessment.

Methenamine hippurate

A meta-analysis from 2021 revealed evidence for a benefit of methenamine hippurate, a urinary tract disinfectant, only when it was used prophylactically (39). In an RCT not included in the meta-analysis, the prophylactic use of methenamine hippurate for 12 months was not inferior to prophylaxis with an antibiotic. The incidence of UTIs requiring antibiotic treatment in women taking an antibiotic prophylactically was 0.89/year; the corresponding figure for prophylactic treatment with methenamine hippurate was 1.38/year (40). Methenamine hippurate is not available in Germany.

Immunostimulation

According to a meta-analysis (e1), oral immunostimulants appear to be suitable for lowering the incidence of rUTI in women. The best-studied drug is OM-89, which can lower the frequency of re-infection, at least over the short term (six months), with an OR of 0.29 [0.10; 0.87]; the difference is insignificant at twelve months (OR 0.69 [0.3; 1.7]). It is therefore stated in the guideline that an attempt to treat with OM-89 can be offered before antibiotics are started. In contrast, parenterally administered Strovac did not lower the rate of rUTI (4). Not included in the meta-analysis is an RCT with MV140, a sublingual preparation of killed bacterial strains. A lowering of the rate of rUTI over 12 months was found, with a number needed to treat (NNT) of 3. 58% [44; 67] of the women treated with MV140 had no further infections in six months, compared to 25% [15; 35] in the placebo group (e2).

No data are available on the efficacy of mannose, methenamine hippurate, or immunostimulation in the geriatric population. The preparations mentioned here are not reimbursable by statutory health insurance in Germany, and some of them are very expensive.

Intravesical instillation

According to a systematic review, the regular intravesical administration of hyaluronic acid and chondroitin sulfate can also lower the rate of rUTI (e3). Both substances are thought to impair the adhesion and are thought to impair the adhesion of bacteria to the urothelium. The therapeutic effect is small (Tabelle 4), and the need to instill these substances through a bladder catheter increases the risk of infection.

Antibiotics for prophylaxis

According to a meta-analysis (e4), the long-term prophylactic use of antibiotics is clinically the most effective preventive measure (RR 0.15; [0.08; 0.29]). It has, therefore, been chosen as the control/comparison treatment in many clinical trials (Table 3). The international guidelines contain recommendations for it with varying strengths (e5).

Table 3

Antibiotics used for continuous prophylaxos or single-dose postcoital use*

Table 4

Treatment options for the prevention of rUTI, with effect strengths

On the other hand, protracted antibiotic treatment increases the risk of adverse drug reactions, such as gastrointestinal symptoms or mycoses, as well as promoting drug resistance, and is therefore rejected by many patients. Short-term and on-demand use (after self-diagnosis) has comparable clinical efficacy, as does single postcoital use (RR 0.15; [0.04; 0.55]) (e4).

A separate meta-analysis (13) is available for postmenopausal women: in this group, too, antibiotic prophylaxis is highly effective (NNT 8.5). Its potential risks and side effects seem to be inadequately documented in the published study reports; for example, no information is given on renal dysfunction.

The systematic search did not identify any studies on older men or nursing home residents. Clinically relevant renal dysfunction is common in the elderly; the patient’s renal function should be tested before antibiotic treatment is begun, and the dosage should be adjusted accordingly (e.g., as suggested in www.dosing.de).

Conclusion

Recurrent UTI occur in both sexes and at all ages. Their diagnosis, treatment, and prevention are challenging. General measures, such as increasing fluid intake and practicing proper hygiene, seem to have no more than a small effect but can usually be implemented easily and without risk. The prophylactic use of antibiotics is only recommended after a thorough risk-benefit analysis. There are special considerations relating to diagnostic evaluation and treatment for vulnerable groups of patients, such as elderly persons living in nursing homes.

Acknowledgment

We thank Ms Gesa Kröger and the UroEvidence team of the German Society of Urology for conducting the systematic literature search and evaluating the literature in the framework of the guideline update.

The revision of the AWMF S3 guideline on the epidemiology, diagnosis, treatment, prevention, and management of uncomplicated, bacterial, community-acquired urinary tract infections in adult patients was financed by the Innovation Fund of the Federal Joint Committee.

Conflict of interest statement
JK has been paid for lectures and presentations by Apogepha Arzneimittel GmbH, Bionorica, GSK, LEO-Pharma, and Janssen Cilag GmbH. She has been reimbursed for travelling expenses by Apogepha Arzneimittel GmbH, Bionorica, GSK, LEO-Pharma, Janssen Cilag GmbH, and MSD. She serves on advisory boards for Bionorica and GSK and as vice-chair of the Working Group for Hygiene and Infectiology of the German Society for Urology (Deutsche Gesellschaft für Urologie e. V.).

GS receives payment for serving on the scientific advisory board of Deximed.

FW received funding from Klosterfrau for a phase 1 trial on the pharmacokinetics of mannose. He serves on advisory boards for Klosterfrau and OM Pharma.

The remaining authors declare that they have no conflict of interest.

Manuscript received on 20 October 2023, revised version accepted on 3 April 2024.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. Guido Schmiemann

Institut für Public Health und Pflegeforschung

Abteilung für Versorgungsforschung/Department for Health Services Research

Universität Bremen

Grazer Str. 4

28359 Bremen, Germany

Cite this as:
Schmiemann G, Kranz J, Mandraka F, Schubert S, Wagenlehner F, Gágyor I: The diagnosis, treatment, and prevention of recurrent urinary tract infection. Dtsch Arztebl Int 2024; 121: 373–82. DOI: 10.3238/arztebl.m2024.0068

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