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Hello urologists, gynaecologists, primary care doctors and all of you that have to deal with urinary tract infections.

Urinary tract infection management and prevention is one of the activities on a routine basis for all caregivers. This newsletter intends to review the last recommendation for managing and preventing urinary infections. Our focus is reducing the number of infections, avoiding antibiotic use when not indicated to prevent resistance and reviewing the evidence about non-antibiotic measures to prevent infections. Scientific support of the evidence and practice guidelines recommendations will be the key to all the information in the newsletter.

We start the newsletter’s first issue with a revision of the main recommendations for diagnosing and preventing recurrent urinary tract infections. It is a high prevalence problem, affecting up to 2.5% of women with a high impact on the quality of life.

Introduction: Epidemiology and risk factors

2 min

Urinary tract infections (UTIs) are the second most frequent reason for medical attention, the most prevalent infectious disease after respiratory infections and the most significant economic burden on healthcare systems (1). It is estimated that more than half of all women will require medical treatment for acute cystitis. In addition, recurrent urinary tract infections sometimes occur, significantly affecting patients' quality and are not always easy to manage. UTIs are considered recurrent in cases of three or more episodes of urinary tract infection per year or at least two in 6 months. Overall, it is estimated that 2.5% of women will have recurrent urinary tract infections (1).

European Association guidelines on Urological Infections revision and recommendations on rUTIs focus on risk factors, diagnosis workup and guidance and the management and prevention.

The main risk factors for rUTIs are age (menopausal status), previous urinary tract infections and a short time between episodes of UTI(2).

Diagnosis

1 min

The diagnosis of UTI is based on the symptoms. Urgency, dysuria, suprapubic pain, urinary frequency, urgency polyuria, foul-smelling urine, haematuria are the main symptoms of UTIs. The presence of at least three symptoms is usually considered diagnostic. Questionnaires as ACSS is a valuable tool in the differential diagnosis of UTIs (3). Diagnosis of rUTI should be confirmed by urine culture. An extensive routine workup, including cystoscopy and urodynamics, is not routinely recommended as the diagnostic yield is low (4).

General hygienic measures

2 min

The first step in preventing recurrent UTIs is identifying possible predisposing factors for an aetiological approach. Next, any urological risk factor must be identified and treated.

Several behavioural and personal hygiene measures have been suggested to increase the risk of rUTI. However, these behavioural modifications have not been demonstrated to be effective but are simple and inexpensive to implement. Among the recommendation, the following points are included (5):

• Proper hydration is advisable, and avoid delaying urination.
• Avoiding constipation
• Postcoital urination
• Daily genital, precoital and postcoital washing from front to back.
• Wearing loose-fitting cotton underwear is recommended.
• Tampons can be used in case of menstruation.
• Showering and bubble baths are discouraged.
• If spermicides are used with or without a diaphragm, alternative methods of contraception should be considered.
• Measures such as compulsive washing of the genital area, often involving the use of soaps or other irritating products, should be avoided.

Prevention with Non-antimicrobial prophylaxis

9 min

Several measures have been proposed to prevent rUTI, including hormonal replacement, extract of American cranberries, D-mannose, probiotics, immunoactive prophylaxis, endovesical instillations with hyaluronic acid and chondroitin sulphate (6). Topical oestrogens are recommended If genital atrophy is present in postmenopausal women. (7). The use of cranberries has shown some weak evidence of beneficial effects in recurrent cystitis. The inconclusive results of the different studies may be related to how different formulations with varying amounts of active ingredients are evaluated (8). The use of cranberry and D-mannose is based on the fact that uropathogenic variants of E. coli have pili on their surface that aid bacterial adhesion by binding to the glycosphingolipids of the renal epithelium.

The recommendation of EAU guidelines on Urological Infections states that the evidence is not sufficient for a recommendation. Therefore, D-mannose should at present only be used within the context of clinical investigations (1). Several scientific studies indicate that regulating gastrointestinal and vaginal flora with probiotics can prevent genitourinary infections. Lactobacillus spp is the main bacteria evaluated. In addition, oral use with Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14; and intravaginal use of Lactobacillus crispatus may prevent the recurrence of UTIs. The primary mechanism of action to explain the activity is considered to be through acidification of the mucosal surface, inhibition of pathogen adhesion, production of substances such as vitamins and immunomodulators, synergy with the individual's immune system.

The use of immunoprophylaxis with oral, intravaginal or intramuscular administration of vaccines obtained from bacterial extracts of uropathogenic strains is a measure that has been evaluated to manage urinary tract infections. Among them, Uro-Vaxon® (OM-89) is more efficient than placebo in several randomised studies than placebo and with a good safety profile (9). Apart from Uro-Vaxon® (OM-89), there are other bacterial extracts to promote immunoprophylaxis against UTIs, including MV140®, Urovac® and ExPEC4V®. The clinical practice guidelines of the European Association of Urology conclude that it can be recommended for use as immunoprophylaxis in women with repeated UTIs(1). Endovesical instillations of hyaluronic acid and chondroitin sulphate have been used for glycosaminoglycan (GAG) layer replenishment to treat interstitial cystitis, overactive bladder, radiation cystitis, and for prevention of rUTI (10). Most of the studies suggest that hyaluronic acid (HA) and chondroitin sulfate (CS) may effectively reduce episodes and symptoms of recurrent urinary tract infections. However, the number of patients included was below one hundred in many pieces of research.

Acidification of the urine has been also evaluated for the prevention of urinary infections with the base that urine pH may have an effect on pathogen growth. Several agents such as ascorbic acid, methionine, gluconic acid, methenamine hippurate and ammonium chloride have been used to get urine acidification (11). It should be also considered that acid pH in the urine may be associated with increased activity of some antimicrobial agents. The fluoroquinolones, co-trimoxazole, aminoglycosides, and macrolides all functioned optimally at alkaline pH, whereas the tetracyclines, nitrofurantoin, and many of the b-lactams tested exhibited their highest activity under more acidic conditions. Urine pH seems that not affect the activity of sulfamethoxazole, oxacillin, amoxicillin and clavulanic acid, vancomycin, imipenem, and clindamycin (12,13). Urine pH values of 5 to 6 are related to higher antimicrobial activity for fosfomycin, the first line antibiotic recommended for urinary tract infections (14). Non-antibiotic measures may be recommended in combination in order to get better results, for instance the research by Pagonas et al demonstrate that non nonantibiotic prophylaxis of recurrent UTIs in renal transplant recipient with L-methionine and cranberry reduce the incidence of urinary tract infections (15).

Conclusion

In conclusion, recurrent urinary tract infections have a significant impact on the quality of life. The first point of treatment is to control possible aetiological factors leading to urinary tract infections. Non-antibiotic measures should be used as first-line treatment to prevent the development of recurrent urinary tract infections.

References

1. Bonkat G, Bartoletti R, Bruyère F, Cai T, Geerlings SE, Köves B, et al. EAU Guidelines on Urological Infections | Uroweb [Internet] 2022 edition. Available on:http://uroweb.org/guideline/urological-infections/ 2. Suskind AM, Saigal CS, Hanley JM, Lai J, Setodji CM, Clemens JQ. Incidence and Management of Uncomplicated Recurrent Urinary Tract Infections in a National Sample of Women in the United States. Urology. 2016;90:50-5. 3. Alidjanov JF, Abdufattaev UA, Makhsudov SA, Pilatz A, Akilov FA, Naber KG, et al. New self-reporting questionnaire to assess urinary tract infections and differential diagnosis: acute cystitis symptom score. Urol Int. 2014;92(2):230-6. 4. van Haarst EP, van Andel G, Heldeweg EA, Schlatmann TJ, van der Horst HJ. Evaluation of the diagnostic workup in young women referred for recurrent lower urinary tract infections. Urology. 2001;57(6):1068-72. 5. Hooton TM. Recurrent urinary tract infection in women. Int J Antimicrob Agents. 2001;17(4):259-68. 6. Medina-Polo J, Arribi Vilela A, Candel González FJ, Salinas Casado J, editores. Actualización de la Infección Urinaria en Urología. Asociación Española de Urología (AEU); 2018. ISBN: 978-84-09-02546-6 7. Beerepoot M J, Geerlings SE, van Haarst EP, van Charante NM, ter Riet G. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J Urol. 2013;190(6):1981-9. 8. Blumberg JB, Camesano TA, Cassidy A, Kris-Etherton P, Howell A, Manach C, et al. Cranberries and their bioactive constituents in human health. Adv Nutr Bethesda Md. 2013;4(6):618-32. 9. Naber KG, Cho YH, Matsumoto T, Schaeffer AJ. Immunoactive prophylaxis of recurrent urinary tract infections: a meta-analysis. Int J Antimicrob Agents. 2009;33(2):111-9. 10. Damiano R, Quarto G, Bava I, Ucciero G, De Domenico R, Palumbo MI, et al. Prevention of recurrent urinary tract infections by intravesical administration of hyaluronic acid and chondroitin sulphate: a placebo-controlled randomised trial. Eur Urol. 2011;59(4):645-51. 11. Burian A, Erdogan Z, Jandrisits C, Zeitlinger M. Impact of pH on Activity of Trimethoprim, Fosfomycin, Amikacin, Colistin and Ertapenem in Human Urine. Pharmacology. 2012;90(5-6):281-7. 12. Yang L, Wang K, Li H, Denstedt JD, Cadieux PA. The Influence of Urinary pH on Antibiotic Efficacy Against Bacterial Uropathogens. Urology. 2014;84(3):731.e1-731.e7. 13. Cengi̇Z M, Hepbostanci G. Impact of pH on the activity of co-used antimicrobials against resistant Escherichia coli strains of animal origin. Turk J Vet Anim Sci. 2020;44(3):747-51. 14. Martín-Gutiérrez G, Docobo-Pérez F, Rodriguez-Beltrán J, Rodríguez-Martínez JM, Aznar J, Pascual A, et al. Urinary Tract Conditions Affect Fosfomycin Activity against Escherichia coli Strains Harboring Chromosomal Mutations Involved in Fosfomycin Uptake. Antimicrob Agents Chemother. 2018;62(1):e01899-17. 15. Pagonas N, Hörstrup J, Schmidt D, Benz P, Schindler R, Reinke P, et al. Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine. Transplant Proc. 2012;44(10):3017-21.