Recurrent uncomplicated urinary tract infections: definitions and risk factors

id000072 10.3205/id000072 urn:nbn:de:0183-id0000727 Review Article Recurrent uncomplicated urinary tract infections: definitions and risk factors Cai Cai Tommaso T MD

Department of Urology, Santa Chiara Hospital, Largo Medaglie d’Oro 9, Trento, Italy, Phone: +39 0461 903306, Mobile phone: +39 3339864943, Fax: +39 0461 903101Department of Urology, Santa Chiara Hospital, Trento, Italy

ktommy@libero.it author German Medical Science GMS Publishing House

Düsseldorf

610 urinary tract infections prophylaxis antibiotics quality of life risk factors Urogenital Infections and Inflammations 20210527 engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). 2195-8831 9 GMS Infectious Diseases GMS Infect Dis 03 Introduction: Recurrent uncomplicated urinary tract infections (UTI) have a high impact on patients’ quality of life and high direct and indirect costs for public health. Therefore, optimal management should be of high priority.Methods: Current international guidelines were reviewed, and a systematic literature search was performed in Medline, Cochrane, and Embase.Results: Several risks factors have been identified and used in everyday clinical practice to plan the correct strategy for recurrence prevention. Among all factors, the most important are: sexual intercourse, spermicide use, having a new sex partner, having a mother with a history of UTI, having had UTI during childhood, and asymptomatic bacteriuria treatment. Moreover, other risk factors such as reduced fluid intake, habitual and post-coital delayed urination, wiping from back to front after defecation, douching and wearing occlusive underwear, as well as irregular bowel function should be taken into account.Conclusions: Recurrent UTI show a high impact on clinical practice. Risk factors are generally related to both virulence of pathogens and patient’s behavior or condition. A recently developed nomogram can assist in identifying women at high risk of symptomatic recurrence that can be suitable candidates for a prophylactic strategy. Summary of recommendationsRecurrent uncomplicated urinary tract infections (rUTI) are defined as at least 3 episodes of a UTI in 12 m</PlainText></TextGroup>onths, or at least two episodes in 6 months.</ListItem><ListItem level="1" levelPosition="2" numString="2.">rUTI have a high impact on public health due to high direct and indirect costs.</ListItem><ListItem level="1" levelPosition="3" numString="3.">Sexual intercourse, spermicide use, having a new sex partner, having a mother with a history of UTI, having had UTI during childhood, and asymptomatic bacteriuria treatment are the most important risk factors for rUTI in young women.</ListItem><ListItem level="1" levelPosition="4" numString="4.">Atrophic vaginitis due to estrogen deficiency, cystocoele, increased post-void urine volume and functional status deterioration are the most important risk factors in old women.</ListItem><ListItem level="1" levelPosition="5" numString="5.">The assessment of all risk factors and the use of a recently validated nomogram could be interesting for identifying women at high risk of symptomatic recurrence that can be suitable candidates for a prophylactic strategy.</ListItem></OrderedList></Pgraph></TextBlock> <TextBlock linked="yes" name="Introduction"> <MainHeadline>Introduction</MainHeadline><Pgraph>Recurrent uncomplicated urinary tract infections (rUTI) may present a big social and economic burden for women of all ages <TextLink reference="1"></TextLink>. Therefore, optimal management of rUTI should be of high priority. This review addresses the definitions and the risk factors of recurrent uncomplicated urinary tract infections (rUTI), with particular attention to the following issues: difference between relapse and reinfections, risk factors in premenopausal and postmenopausal women, and the role of a validated nomogram and questionnaires for the calculation of the risk of a new episode of rUTI. The review does not address recurrent UTI in case of significant underlying anatomical or functional abnormalities of the urinary tract, which need a different approach.</Pgraph></TextBlock> <TextBlock linked="yes" name="Methods"> <MainHeadline>Methods</MainHeadline><Pgraph>This review incorporates the 2016 Guidelines on Urological Infections of the European Association of Urology (EAU) and the latest Infectious Diseases Society of America Guideline for the Management of Asymptomatic Bacteriuria <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>. Furthermore, the previous version of the ICUD textbook on Urological infections has been updated and was included <TextLink reference="4"></TextLink>. Moreover, a systematic literature search was performed in Medline, Cochrane, and Embase. The systematic literature search covered the period fro<TextGroup><PlainText>m 1</PlainText></TextGroup>979 to 2019. The following keywords were used: recurrent urinary tract infections, epidemiology, and ris<TextGroup><PlainText>k f</PlainText></TextGroup>actors. The limitations used included adults aged ≥1<TextGroup><PlainText>8 y</PlainText></TextGroup>ears, clinical studies, review article, English, and peer reviewed. A total of 561 publications were identified and screened by title and abstract. Finally, <TextGroup><PlainText>7 p</PlainText></TextGroup>apers were included in the review (Table 1 <ImgLink imgNo="1" imgType="table"/>). The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using ICUD standards (EAU guidelines 2020 <TextLink reference="2"></TextLink>) (Table 1 <ImgLink imgNo="1" imgType="table"/>).</Pgraph></TextBlock> <TextBlock linked="yes" name="Results"> <MainHeadline>Results</MainHeadline><SubHeadline>Definition, context and clinical application</SubHeadline><Pgraph>Recurrent urinary tract infections (rUTI) are defined as at least 3 episodes of a UTI in 12 months, or at least <TextGroup><PlainText>2 e</PlainText></TextGroup>pisodes in 6 months <TextLink reference="1"></TextLink>, <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>, <TextLink reference="5"></TextLink>. Recurrent UTI can be divided into two subgroups:</Pgraph><Pgraph><UnorderedList><ListItem level="1">relapses</ListItem><ListItem level="1">reinfections.</ListItem></UnorderedList></Pgraph><Pgraph><Mark2>Relapse:</Mark2> is defined as a UTI caused by the same microo<TextGroup><PlainText>rgani</PlainText></TextGroup>sm after adequate treatment <TextLink reference="3"></TextLink>. <Mark2>Reinfection:</Mark2> is defined as a recurrence of a UTI caused by a different microorganism, or a recurrent UTI caused by a previously isolated microorganism after treatment and a subsequent negative urine culture <TextLink reference="3"></TextLink>, <TextLink reference="5"></TextLink>.</Pgraph><Pgraph>This classification shows important clinical issues: relapses signify that the original infection has never been eradicated. The organism cultured is identical to that from the previous episode, and symptoms usually recur within 2 weeks of the end of treatment for the previous episode. If the previous episode was treated with short-course therapy, the first thought should be that there was subclinical pyelonephritis and that a longer course of treatment is needed. If a longer course is followed by another relapse, ‘imaging’ (CT scan or ultrasound) is advisable to look for an anatomic abnormality <TextLink reference="6"></TextLink>, <TextLink reference="7"></TextLink>.</Pgraph><SubHeadline>Epidemiology of rUTI</SubHeadline><Pgraph>After an initial urinary tract infection, approximately 20–30% of women with a UTI will have a second UTI within 6 months, and 3% will experience a third UTI during that time period <TextLink reference="8"></TextLink>. Recurrent UTI are common among young healthy women even though they generally have anatomically and physiologically normal urinary tracts and are associated with considerable morbidity and e<TextGroup><PlainText>xpens</PlainText></TextGroup>e <TextLink reference="9"></TextLink>, <TextLink reference="10"></TextLink>. In detail, it is estimated that in young women overall, there are 0.5 episodes of acute cystitis per person per year, and the incidence decreases with age <TextLink reference="11"></TextLink>. In postmenopausal women, it is estimated that there are 0.07 episodes of acute cystitis per person per year <TextLink reference="7"></TextLink>, <TextLink reference="12"></TextLink>, <TextLink reference="13"></TextLink>. Most recurrences occur within the first 3 months after the primary infection. When the initial infection is caused by <Mark2>Escherichia coli</Mark2>, there is a higher risk of reinfection within the first 6 months <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>.</Pgraph><SubHeadline>Risk factors</SubHeadline><Pgraph>Risk factors are different between young (premenopausal) and old (postmenopausal) women. This difference shows important clinical relevance.</Pgraph><SubHeadline2>Young women</SubHeadline2><Pgraph>In young healthy women, sexual intercourse is the risk factor most highly associated with recurrent UTI <TextLink reference="10"></TextLink>. Other risk factors in young women include spermicide use, having a new sexual partner, having a mother with a history of UTI, and having had a UTI during childhood <TextLink reference="15"></TextLink>. There are several behaviors that are thought to increase the risk of recurrent UTI, but their association with UTI has not been clearly demonstrated in trials <TextLink reference="10"></TextLink>. These include reduced fluid intake, habitually delaying urination, delaying post-coital urination, wiping from back to front after defecation, douching, and wearing occlusive underwear <TextLink reference="10"></TextLink>. Finally, dysfunctional voiding patterns in which there is increased tone of the external sphincter during micturition can also be associated with recurrent UTI in otherwise urologically normal women <TextLink reference="15"></TextLink>.</Pgraph><SubHeadline3>Sexual intercourse</SubHeadline3><Pgraph>Any lifetime sexual activity and any sexual activity during the past year were the variables most strongly associat<TextGroup><PlainText>ed w</PlainText></TextGroup>ith the risk of recurrence in young women <TextLink reference="16"></TextLink>. I<TextGroup><PlainText>n detail, sexu</PlainText></TextGroup>al intercourse in the past month has been associated with a risk of more than 9 times to develop UTI [OR 10.3 (5.8 to 18.3)] <TextLink reference="16"></TextLink>. In particular, young w<TextGroup><PlainText>ome</PlainText></TextGroup>n with recurrent UTI were more likely to report exposure to spermicides and to oral contraceptives <TextLink reference="16"></TextLink>. Both intercourse and spermicide exposure increase periurethral <Mark2>Escherichia coli</Mark2> colonization, and such colonization occurs more frequently and for prolonged periods in women with rUTI <TextLink reference="17"></TextLink>, <TextLink reference="18"></TextLink>.</Pgraph><SubHeadline3>History of UTI in the mother and a history of early UTI onset in the woman herself</SubHeadline3><Pgraph>The history of UTI in the mother and a history of early UTI onset in the young woman herself were associated with a 2–4-fold increase in the risk of recurrence. These two variables were the most strongly associated with the risk of recurrence, after the strongest variable, recent frequency of sexual intercourse <TextLink reference="16"></TextLink>. In particular, Kunin showed that girls who experienced these infections during childhood were more prone to bacteriuria and symptomatic infections as adults <TextLink reference="19"></TextLink>.</Pgraph><SubHeadline3>Bowel function and water intake</SubHeadline3><Pgraph>Fecal-perineal-urethral contamination is the most probable explanation for infections caused by enteric bacteria in women, as shown by several authors evaluating th<TextGroup><PlainText>e g</PlainText></TextGroup>enotype of <Mark2>Escherichia coli</Mark2> strains causing UTI in women <TextLink reference="20"></TextLink>. Loening-Baucke et al., evaluating a cohort of 23<TextGroup><PlainText>4 c</PlainText></TextGroup>hronically constipated and encopretic children with a mean follow-up of 15 months, showed that constipation treatment resulted in the disappearance of daytime urinary incontinence in 89%, and night-time urinary incontinence in 63% of patients, as well as disappearance of rUTI in all patients who had no anatomical abnormality of the urinary tract <TextLink reference="21"></TextLink>. With regard to water intake, literature data are discordant. Eckford et al. documented a reduction of recurrent UTI in premenopausal women with adequate hydratation with urine osmolality <1105, using an osmolality probe at home, whereas other studies did not find the same correlation <TextLink reference="22"></TextLink>. Nygaard et al. surveyed female teachers and found that women who drank less had a 2.21-fold higher risk (95% CI 1.45–3.38) of UTI compared to women who drank the volume they desired at work <TextLink reference="23"></TextLink>.</Pgraph><SubHeadline3>Asymptomatic bacteriuria treatment</SubHeadline3><Pgraph>Recently, Cai et al. found that antibiotic treatment of asymptomatic bacteriuria in young women with recurrent UTI is not only unnecessary, but harmful <TextLink reference="24"></TextLink>, <TextLink reference="25"></TextLink>. In fact, they found that in women who had undergone antibiotic treatment, the rate of <Mark2>E. coli</Mark2> decreased over time, whereas the prevalence of <Mark2>E. faecalis</Mark2> increased gradually, suggesting that <Mark2>E. faecalis</Mark2> should be an important defense mechanism that effectively interferes with the establishment of many important enteric pathogens, such as <Mark2>E. coli</Mark2> <TextLink reference="24"></TextLink>.</Pgraph><SubHeadline2>Old women</SubHeadline2><Pgraph>The incidence of UTI in women increases with advancing age <TextLink reference="15"></TextLink>. In a placebo-controlled, double-blind study, Ra<TextGroup><PlainText>z e</PlainText></TextGroup>t al. showed a correlation between reduced estrogenic hormone levels after menopause and the development of recurrent UTI, highlighting the fact that estrogens stimulate proliferation of <Mark2>Lactobacillus</Mark2> in the vaginal epithelium, causing reduction of vaginal pH, thereby preventing vaginal colonization by Enterobacteriaceae <TextLink reference="26"></TextLink>. Recently, Lüthje et al. highlighted that estrogen induced the expression of antimicrobial peptides, thereby enhancing the antimicrobial capacity of the urothelium and restricting bacterial multiplication <TextLink reference="27"></TextLink>. Furthermore, they suggested the application of estrogen in postm<TextGroup><PlainText>enopausa</PlainText></TextGroup>l women suffering from recurrent UTI <TextLink reference="27"></TextLink>. Moreover, in older women, risk factors include urinary incontinence, history of UTI before menopause, blood group antigen nonsecretor status, and having a cystocele and an increased post-void residual.</Pgraph><SubHeadline>Nomogram and tools for risk of recurrence calculation</SubHeadline><Pgraph>Hooton et al. developed a simple risk prediction model by using the information about the number of days with intercourse and contraceptive use (diaphragm and spermicide) for predicting the risk of UTI recurrence <TextLink reference="7"></TextLink>. They found that an unmarried, 24-year-old female university student who had sexual intercourse without a diaphragm and spermicide on three of the past seven days had a risk of UTI that was 2.6-fold greater than that of a similar student who had not had intercourse in the previous week <TextLink reference="7"></TextLink>. This study highlights the role of recurrence risk prediction tools in the management of women with UTI. In 2014, Cai T et al., for the first time, developed and validated an easy nomogram based on several parameters both from the patients and the bacteria for predicting the recurrence of UTI risk <TextLink reference="28"></TextLink>. The nomogram was evaluated by calculating concordance probabilities, as well as testing calibration of predicted urinary tract infection recurrence with observed urinary tract infections. Nomogram variables included: number of partners <TextLink reference="29"></TextLink>, bowel function, type of pathogens isolated (gram-positive/negative), hormonal status, number of previous urinary tract infection recurrences and previous treatment of asymptomatic bacteriuria. The nomogram accurately predicts the recurrence risk of urinary tract infection at 12 months, and can assist in identifying women at high risk of symptomatic recurrence that can be suitable candidates for a prophylactic strategy (Figure 1 <ImgLink imgNo="1" imgType="figure"/>) <TextLink reference="28"></TextLink>. In order to calculate the recurrence probability, the patient values are identified on each axis, then for each onea vertical line upwards to the “points” axis is drawn. This determines how many points each variable generates. All points for all variables are added, and this sum is placed on the ‘total points’ line. Then a vertical line downwards from this point is drawn, and the recurrence risk probability at 12 months is identified <TextLink reference="28"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Conclusions"> <MainHeadline>Conclusions</MainHeadline><Pgraph>Recurrent UTI represent a major social and economic burden for women of all ages. Risk factors for recurrent UTI are generally related to both virulence of pathogens (such as <Mark2>Escherichia coli</Mark2> adherent to vaginal and bladder epithelial cells, asymptomatic bacteriuria treatment) and patient’s behavior or condition (such as use of a spermicide or a diaphragm, delayed postcoital micturition, or the ABO-blood-group non-secretor phenotype). A recently developed nomogram can assist in identifying women at high risk of symptomatic recurrence that can be suitable candidates for a prophylactic strategy.</Pgraph></TextBlock> <TextBlock linked="yes" name="Note"> <MainHeadline>Note</MainHeadline><Pgraph>This article will also be published as a chapter of the L<TextGroup><PlainText>ivin</PlainText></TextGroup>g Handbook “Urogenital Infections and Inflammations” <TextLink reference="30"></TextLink>.</Pgraph></TextBlock> <TextBlock linked="yes" name="Competing interests"> <MainHeadline>Competing interests</MainHeadline><Pgraph>The author declares that he has no competing interests.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Wagenlehner F</RefAuthor> <RefAuthor>Wullt B</RefAuthor> <RefAuthor>Ballarini S</RefAuthor> <RefAuthor>Zingg D</RefAuthor> <RefAuthor>Naber KG</RefAuthor> <RefTitle>Social and economic burden of recurrent urinary tract infections and quality of life: a patient web-based study (GESPRIT)</RefTitle> <RefYear>2018</RefYear> <RefJournal>Expert Rev Pharmacoecon Outcomes Res</RefJournal> <RefPage>107-17</RefPage> <RefTotal>Wagenlehner F, Wullt B, Ballarini S, Zingg D, Naber KG. 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Available from: http://www.icud.info/PDFs/ICUD%20Urogenital%20Infections.pdf</RefTotal> <RefLink>http://www.icud.info/PDFs/ICUD%20Urogenital%20Infections.pdf</RefLink> </Reference> </References> <Media> <Tables> <Table format="png"> <MediaNo>1</MediaNo> <MediaID>1</MediaID> <Caption><Pgraph><Mark1>Table 1: Studies evaluated after systematic review (1979–2019)</Mark1></Pgraph></Caption> </Table> <NoOfTables>1</NoOfTables> </Tables> <Figures> <Figure format="png" height="467" width="643"> <MediaNo>1</MediaNo> <MediaID>1</MediaID> <Caption><Pgraph><Mark1>Figure 1: LUTIRE nomogram [27]</Mark1></Pgraph></Caption> </Figure> <NoOfPictures>1</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>