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Preventing urinary tract infections after menopause without antibiotics
Maturitas 99 (2017) 43–46
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Preventing urinary tract infections after menopause without antibiotics Marta Caretto, Andrea Giannini, Eleonora Russo, Tommaso Simoncini ∗ University of Pisa, Italy
a r t i c l e
i n f o
Article history: Received 30 January 2017 Accepted 6 February 2017 Keywords: Urinary tract infection Postmenopausal women
a b s t r a c t Urinary tract infections (UTIs) are the most common bacterial infections in women, and increase in incidence after the menopause. It is important to uncover underlying abnormalities or modifiable risk factors. Several risk factors for recurrent UTIs have been identified, including the frequency of sexual intercourse, spermicide use and abnormal pelvic anatomy. In postmenopausal women UTIs often accompany the symptoms and signs of the genitourinary syndrome of menopause (GSM). Antimicrobial prophylaxis has been demonstrated to be effective in reducing the risk of recurrent UTIs in women, but this may lead to drug resistance of both the causative microorganisms and the indigenous flora. The increasing prevalence of Escherichia coli (the most prevalent uropathogen) that is resistant to antimicrobial agents has stimulated interest in novel non-antibiotic methods for the prevention of UTIs. Evidence shows that topical estrogens normalize vaginal flora and greatly reduce the risk of UTIs. The use of intravaginal estrogens may be reasonable in postmenopausal women not taking oral estrogens. A number of other strategies have been used to prevent recurrent UTIs: probiotics, cranberry juice and d-mannose have been studied. Oral immunostimulants, vaginal vaccines and bladder instillations with hyaluronic acid and chondroitin sulfate are newer strategies proposed to improve urinary symptoms and quality of life. This review provides an overview of UTIs’ prophylaxis without antibiotics, focusing on a practical clinical approach to women with UTIs. © 2017 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
UTIs in ageing women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Strategies to prevent and manage UTIs in ageing women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Estrogens and UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Vitamin D and UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Use of probiotics for the prevention and treatment of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Cranberry in the prevention and treatment of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 d-Mannose and UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Newer concepts in the prevention and treatment of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Research agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
∗ Corresponding author at: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Italy. E-mail address: [email protected] (T. Simoncini). http://dx.doi.org/10.1016/j.maturitas.2017.02.004 0378-5122/© 2017 Elsevier B.V. All rights reserved.
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M. Caretto et al. / Maturitas 99 (2017) 43–46
1. UTIs in ageing women Urinary tract infections (UTIs) are the most common bacterial infections in women and their incidence rises dramatically in postmenopausal women. Approximately 20%–30% of women with UTIs will have a recurrence. Recurrent UTIs (rUTIs) are defined as at least three episodes of UTIs in twelve months, or at least two episodes in six months. rUTIs can be a relapse or a reinfection. A relapse refers to UTIs caused by the same microorganism after adequate treatment. Reinfections are rUTIs caused by a different microorganism or by a previously isolated microorganism after treatment and a subsequent negative urine culture. The majority of rUTIs is caused by reinfection from extraurinary sources such as the rectum or vagina: uropathogenic Escherichia coli (UPEC)is now known to invade urothelial cells and form a quiescent intracellular bacterial reservoir [1]. The first step in the management of rUTIs is to obtain a detailed history, including information about previously UTIs’ episodes, menopausal status, recent antibiotic use, and sexual history, including number of partners, spermicide use and use of barrier contraceptives. The second step is a physical examination: complete pelvic examination to analyze vaginal epithelium, urinary incontinence (UI), the presence or absence of pelvic organ prolapse (POP) [2]. Antibiotics, even at low-doses, are effective in the treatment and prophylaxis of UTIs but lead to an increase antibiotic resistance in microorganisms [3]. 2. Strategies to prevent and manage UTIs in ageing women Several strategies have been proposed for preventing rUTIs and the first is a change in behavior. It is reasonable to suggest to women with rUTIs a different contraceptive (avoiding spermicides) or early postcoital voiding and more liberal fluid intake to increase the frequency of micturition [4]. 3. Estrogens and UTIs Menopausal estrogen withdrawal is associated with a decrease in volume of the vaginal muscles and of the muscles of the pelvic floor. This, along with the vascular changes in the pelvic and periurethral districts and with the increases looseness of the pelvic ligaments favors the development of UI and POP [5]. Estrogen stimulates the proliferation of lactobacillus, reduces vaginal pH, and avoids vaginal colonization of Enterobacteriaceae. Pabich et al. have studied the association between UTIs and other peculiarities of ageing women (incontinence, diabetes, the use of HRT), with vaginal microbial flora. Their data suggest that the restoration of vaginal lactobacilli via topical estrogen in postmenopausal women with rUTIs could be associated with a marked reduction in UTIs incidence [6]. Systemic estrogens are rarely a clinical option for older women. However, vaginal estrogens remain a life-long opportunity to treat vulvo-vaginal atrophy (VVA) even at later stages in life, and this is considered a viable option to prevent UTIs, as well. Indeed, a trial performed by Raz and Stamm [7] and a study by Eriksen [8] show that vaginal estrogens significantly reduced the incidence of UTIs and the frequency of urogenital symptoms, such as VVA and UI. However, contradicting results are found in the literature: another study showed that the use of vaginal estrogens is less effective to prevent rUTIs than antibiotic therapy. In conclusion, in postmenopausal women there is a trend toward fewer UTIs recurrences with vaginal estrogens, which was not seen with oral estrogens. Vaginal estrogens are safe and effective [9], however long-term adherence is an issue with most patients, with high dropout rates. The recent introduction of
Ospemifene, an orally available selective estrogen receptor modulator with the indication of prevention and treatment of VVA, may represent a new option for those patients who are intolerant to long-term use of vaginal estrogens. However, data on its possible effect on UTIs prevention are currently missing [10]. 4. Vitamin D and UTIs Vitamin D could enhance cathelicidin production in the urinary tract and thereby help protecting from microbial invasion. This could make 25-OH D3 an effective and safe way of activating the endogenous antimicrobial response locally at the site of infection [11]. Restoring proper vitamin D levels in postmenopausal women with a history of rUTIs may therefore help the bladder epithelium to prepare a stronger and faster immune response once bacteria enter the bladder. 5. Use of probiotics for the prevention and treatment of UTIs Vaginal lactobacilli have protective roles: they are able to produce antimicrobial compounds such as lactic acid, hydrogen peroxide; to produce a biosurfactant that inhibits the adhesion of uropathogens to surfaces; and to stimulate non-specific innate immune system. Restoration of vaginal flora with lactobacilli using probiotics is an effective strategy to decrease the frequency of UTIs. A recent study suggests that the administration of vaginal suppositories containing L. crispatus GAI 98332 is safe and effective in preventing rUTIs. Evidence show that L. rhamnosus Gr-1 and L. fermentum-RC can also colonize the vagina. However, clinical studies that determine the optimal dosage, duration and mode of lactobacilli delivery for establishing vaginal and/or periurethral colonization are still lacking [12]. 6. Cranberry in the prevention and treatment of UTIs Cranberry contains a proanthocyanidin that counteracts bladder colonization by E. coli by inhibiting the attachment of bacteria to the uroepithelial mucosa. Anti-inflammatory activity of cranberry extract prevents the development of symptoms but also to lower intercellular bacterial propagation, and thus reduces the frequency of UTIs and the propensity towards chronic infection. Evidence shows that consumption of cranberry juice significantly reduces clinical UTIs’ episodes in women with a history of UTIs in the previous year and antibiotic use for treatment of these events [13]. A more recent Cochrane review reports a nonsignificant reduction in risk of rUTIs with cranberry treatment and a study by Juthani-Mehta et al. supports the view that cranberry products should not be recommended as a medical intervention for the prevention of rUTIs [14]. In spite of these data, literature as well as expert opinion is still conflicting on the clinical role of cranberry to prevent UTIs. In the wake of conclusive data, cranberry remains a popular and safe approach in the management of UTIs. 7. d-Mannose and UTIs d-Mannose is a simple sugar, a monosaccharide, closely related to glucose. d-Mannose is rapidly absorbed and then excreted by the urinary tract. The bladder wall is coated with various mannosilate proteins, such as Tamm-Horsfall protein (THP) that interfere directly with the adhesion of bacteria on the mucosa. THP may fasten to E. coli with a specific bond, which may be inhibited by exogenous d-mannose. This provides the rationale for use of d-
M. Caretto et al. / Maturitas 99 (2017) 43–46
45
Fig. 1. Preventing urinary tract infections after menopause without antibiotics.
mannose in the treatment of UTIs, particularly determined by E. coli. Many studies, including that of Vicariotto et al. [15], show that hallmark symptoms of UTIs are significantly improved by d-mannose. Another study from Domenici and colleagues is confirmatory. Additional studies are needed to support and validate these preliminary results [16].
8. Newer concepts in the prevention and treatment of UTIs The oral immunostimulant, OM-89, is an extract of 18 different serotypes of heat killed uropathogenic E. coli, which stimulates innate immunity by increasing neutrophils and macrophage phagocytosis. OM-89 shows promise in the prevention of recurrent UTIs [17]. A similar concept is provided by the vaginal vaccine, Urovac: it contains 10 heat killed uropathogenic bacteria including 6 different serotypes of UPEC, and 1 strain each of Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii and Enterococcus faecalis. This vaccine primarily induces humoral immunity in the urogenital tract [18]. A new therapy based on the reinstatement of the glycosaminoglycan (GAG) bladder epithelium has recently been proposed for the treatment of rUTIs. This GAG layer consists of non-sulfated, for example, hyaluronic acid (HA), and sulfated, for example, heparan sulfate and heparin, chondroitin sulfate (CS), GAG. Ciani et al. perform a European retrospective multicentre study to compare the clinical effectiveness of bladder instillations of GAG versus standard
management of rUTIs in adult women [19]. However, large-scale studies are needed to underline the benefit of this therapy.
9. Conclusions The use of vaginal estrogen, oral and vaginal probiotics, cranberry prophylaxis is backed up by growing evidence of efficacy. d-Mannose is also emerging as an effective treatment, although larger studies are needed to confirm its efficacy. Newer strategies including modern adherence inhibitors or immunologic interventions are needed to broaden the therapeutic portfolio in the hands of physicians (Fig. 1). Recurrent UTIs represent a common and distressing problem for ageing women. UTIs are also costly for the health care system. A wiser use of antimicrobial therapy is needed, particularly in elderly women. Hence, non-antibiotic therapies are important in this age group, and it is key to strengthen the evidence on the safety and efficacy of the available therapeutic strategies to path the way to improved efficacy and cost-effectiveness.
10. Practice points Recurrent urinary tract infections (rUTIs) are common in ageing women. The majority of recurrences are reinfection from extraurinary sources, such as the rectum or vagina. Vaginal estrogens reduce the incidence of UTIs. Probiotics, cranberry extracts and d-mannose are effective in reducing the risk of UTIs.
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M. Caretto et al. / Maturitas 99 (2017) 43–46
11. Research agenda Further wide-scale randomized studies are needed to establish the role of estrogen therapy, probiotics and lactobacilli, as well as to identify other possible methods to reduce the use of antibiotics. Contributors All authors reviewed the literature, prepared and edited the manuscript. Conflict of interest The authors declare that they have no conflict of interest. Funding No funding was received for the preparation of this review. Provenance and peer review Peer review was directed by Prof. Margaret Rees independently of Tommaso Simoncini (one of the authors and an Editor of Maturitas), who was blinded to the process. References [1] D. Hickling, V. Nitti, Management of recurrent urinary tract infections in healthy adult women, Rev. Urol. 15 (2) (2013) 41–48. [2] Hyun-Kyung Kim, So-Yeon Kang, Youn-Jee Chung, Jang-Heub Kim, Mee-Ran Kim, The recent review of the genitourinary syndrome of menopause, J. Menopausal Med. 21 (2) (2015) 65–71. [3] R. Raz, Urinary tract infection in postmenopausal women. Review article, Korean J. Urol. 52 (12) (2011) 801–808. [4] M. Beerepoot, S. Geerlings, Non-antibiotic prophylaxis for urinary tract infections, Pathogens 5 (2) (2016) 36. [5] P. Mannella, G. Palla, M. Bellini, T. Simoncini, The female pelvic floor through midlife and aging, Maturitas 76 (2013) 230–234. [6] W.L. Pabich, S. Fihn, W. Stamm, D. Scholes, E.-J. Boyko, K. Gupta, Prevalence and determinants of vaginal flora alterations in postmenopausal women, J. Infect. Dis. 188 (7P) (2003) 1054–1058.
[7] R. Raz, R. Colodner, Y. Rohana, S. Battino, E. Rottensterich, I. Wasser, W. Stamm, Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women, Clin. Infect. Dis. 1 (36(11)) (2003) 1362–1368. [8] B. Eriksen, A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women, Am. J. Obstet. Gynecol. 180 (1999) 1072–1079. [9] E.C.M. Neves, M. Birkhauser, G. Samsioe, I. Lambrinoudaki, S. Palacios, R.S. Borrego, et al., EMAS position statement: the ten point guide to the integral management of menopausal health, Maturitas 81 (2015) 88–92. [10] S. Palacios, C. Castelo-Branco, H. Currie, et al., Update on management of genitourinary syndrome of menopause: a practical guide, Maturitas 82 (2015) 308–313. [11] W. Nseir, et al., The association between serum level of vitamin D and recurrent urinary tract infections in premenopausal women, Int. J. Infect. Dis. 2013 (2016) 1021–9712. [12] Shinya Ueharaa, Koichi Mondena, Koji Nomotob, Yuko Senoa, Reiko Kariyamaa, Hiromi Kumona A pilot study evaluating the safety and effectiveness of Lactobacillus vaginal suppositories in patients with recurrent urinary tract infection, Int. J. Antimicrob. Agents (2006) S30–S34. [13] Kevin C Maki, Kerrie L Kaspar, Christina Khoo, Linda H Derrig, Arianne L. Schild, Kalpana Gupta, Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection, Am. Soc. Nutr. 103 (6) (2016) 1434–1442. [14] E. Lindsay, Cranberry for prevention of urinary tract infection? Time to move on, JAMA 316 (November (18)) (2016) 1873–1874. [15] Vicariotto Effectiveness of an association of a cranberry dry extract, d-Mannose, and the two microorganisms Lactobacillus plantarum LP01 and Lactobacillus paracasei LPC09 in women affected by cystitis: a pilot study, J. Clin. Gastroenterol. 48 (November–December, Suppl. 1) (2014) S96–101. [16] L. Domenici, M. Monti, C. Bracchi, M. Giorgini, V. Colagiovanni, L. Muzii, P. Benedetti Panici, d-Mannose: a promising support for acute urinary tract infections in women. A pilot study, Eur. Rev. Med. Pharmacol. Sci. 20 (2016) 2920–2925. [17] M. Huber, K. Krauter, G. Winkelmann, H.W. Bauer, V.W. Rahlfs, P.A. Lauener, G.S. Blessmann, W.G. Bessler, Immunostimulation by bacterial components: II. Efficacy studies and meta-analysis of the bacterial extract OM-89, Int. J. Immunopharmacol. 22 (2000) 1103. [18] W.J. Hopkins, J. Elkahwaji, L.M. Beierle, G.E. Leverson, D.T. Uehling, Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial, J. Urol. 177 (2007) 134. [19] O. Ciani, E. Arendsen, M. Romancik, R. Lunik, E. Costantini, M. Di Biase, G. Morgia, E. Fragalà, T. Roman, M. Bernat, G. Guazzoni, R. Tarricone, M. Lazzeri, Intravesical administration of combined hyaluronic acid (HA) and chondroitin sulfate (CS) for the treatment of female recurrent urinary tract infections: a European multicentre nested case-control study, BMJ 6 (March (3)) (2016).
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Preventing urinary tract infections after menopause without antibiotics Marta Caretto, Andrea Giannini, Eleonora Russo, Tommaso Simoncini ∗ University of Pisa, Italy
a r t i c l e
i n f o
Article history: Received 30 January 2017 Accepted 6 February 2017 Keywords: Urinary tract infection Postmenopausal women
a b s t r a c t Urinary tract infections (UTIs) are the most common bacterial infections in women, and increase in incidence after the menopause. It is important to uncover underlying abnormalities or modifiable risk factors. Several risk factors for recurrent UTIs have been identified, including the frequency of sexual intercourse, spermicide use and abnormal pelvic anatomy. In postmenopausal women UTIs often accompany the symptoms and signs of the genitourinary syndrome of menopause (GSM). Antimicrobial prophylaxis has been demonstrated to be effective in reducing the risk of recurrent UTIs in women, but this may lead to drug resistance of both the causative microorganisms and the indigenous flora. The increasing prevalence of Escherichia coli (the most prevalent uropathogen) that is resistant to antimicrobial agents has stimulated interest in novel non-antibiotic methods for the prevention of UTIs. Evidence shows that topical estrogens normalize vaginal flora and greatly reduce the risk of UTIs. The use of intravaginal estrogens may be reasonable in postmenopausal women not taking oral estrogens. A number of other strategies have been used to prevent recurrent UTIs: probiotics, cranberry juice and d-mannose have been studied. Oral immunostimulants, vaginal vaccines and bladder instillations with hyaluronic acid and chondroitin sulfate are newer strategies proposed to improve urinary symptoms and quality of life. This review provides an overview of UTIs’ prophylaxis without antibiotics, focusing on a practical clinical approach to women with UTIs. © 2017 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
UTIs in ageing women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Strategies to prevent and manage UTIs in ageing women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Estrogens and UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Vitamin D and UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Use of probiotics for the prevention and treatment of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Cranberry in the prevention and treatment of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 d-Mannose and UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Newer concepts in the prevention and treatment of UTIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Practice points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Research agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
∗ Corresponding author at: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Italy. E-mail address: [email protected] (T. Simoncini). http://dx.doi.org/10.1016/j.maturitas.2017.02.004 0378-5122/© 2017 Elsevier B.V. All rights reserved.
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1. UTIs in ageing women Urinary tract infections (UTIs) are the most common bacterial infections in women and their incidence rises dramatically in postmenopausal women. Approximately 20%–30% of women with UTIs will have a recurrence. Recurrent UTIs (rUTIs) are defined as at least three episodes of UTIs in twelve months, or at least two episodes in six months. rUTIs can be a relapse or a reinfection. A relapse refers to UTIs caused by the same microorganism after adequate treatment. Reinfections are rUTIs caused by a different microorganism or by a previously isolated microorganism after treatment and a subsequent negative urine culture. The majority of rUTIs is caused by reinfection from extraurinary sources such as the rectum or vagina: uropathogenic Escherichia coli (UPEC)is now known to invade urothelial cells and form a quiescent intracellular bacterial reservoir [1]. The first step in the management of rUTIs is to obtain a detailed history, including information about previously UTIs’ episodes, menopausal status, recent antibiotic use, and sexual history, including number of partners, spermicide use and use of barrier contraceptives. The second step is a physical examination: complete pelvic examination to analyze vaginal epithelium, urinary incontinence (UI), the presence or absence of pelvic organ prolapse (POP) [2]. Antibiotics, even at low-doses, are effective in the treatment and prophylaxis of UTIs but lead to an increase antibiotic resistance in microorganisms [3]. 2. Strategies to prevent and manage UTIs in ageing women Several strategies have been proposed for preventing rUTIs and the first is a change in behavior. It is reasonable to suggest to women with rUTIs a different contraceptive (avoiding spermicides) or early postcoital voiding and more liberal fluid intake to increase the frequency of micturition [4]. 3. Estrogens and UTIs Menopausal estrogen withdrawal is associated with a decrease in volume of the vaginal muscles and of the muscles of the pelvic floor. This, along with the vascular changes in the pelvic and periurethral districts and with the increases looseness of the pelvic ligaments favors the development of UI and POP [5]. Estrogen stimulates the proliferation of lactobacillus, reduces vaginal pH, and avoids vaginal colonization of Enterobacteriaceae. Pabich et al. have studied the association between UTIs and other peculiarities of ageing women (incontinence, diabetes, the use of HRT), with vaginal microbial flora. Their data suggest that the restoration of vaginal lactobacilli via topical estrogen in postmenopausal women with rUTIs could be associated with a marked reduction in UTIs incidence [6]. Systemic estrogens are rarely a clinical option for older women. However, vaginal estrogens remain a life-long opportunity to treat vulvo-vaginal atrophy (VVA) even at later stages in life, and this is considered a viable option to prevent UTIs, as well. Indeed, a trial performed by Raz and Stamm [7] and a study by Eriksen [8] show that vaginal estrogens significantly reduced the incidence of UTIs and the frequency of urogenital symptoms, such as VVA and UI. However, contradicting results are found in the literature: another study showed that the use of vaginal estrogens is less effective to prevent rUTIs than antibiotic therapy. In conclusion, in postmenopausal women there is a trend toward fewer UTIs recurrences with vaginal estrogens, which was not seen with oral estrogens. Vaginal estrogens are safe and effective [9], however long-term adherence is an issue with most patients, with high dropout rates. The recent introduction of
Ospemifene, an orally available selective estrogen receptor modulator with the indication of prevention and treatment of VVA, may represent a new option for those patients who are intolerant to long-term use of vaginal estrogens. However, data on its possible effect on UTIs prevention are currently missing [10]. 4. Vitamin D and UTIs Vitamin D could enhance cathelicidin production in the urinary tract and thereby help protecting from microbial invasion. This could make 25-OH D3 an effective and safe way of activating the endogenous antimicrobial response locally at the site of infection [11]. Restoring proper vitamin D levels in postmenopausal women with a history of rUTIs may therefore help the bladder epithelium to prepare a stronger and faster immune response once bacteria enter the bladder. 5. Use of probiotics for the prevention and treatment of UTIs Vaginal lactobacilli have protective roles: they are able to produce antimicrobial compounds such as lactic acid, hydrogen peroxide; to produce a biosurfactant that inhibits the adhesion of uropathogens to surfaces; and to stimulate non-specific innate immune system. Restoration of vaginal flora with lactobacilli using probiotics is an effective strategy to decrease the frequency of UTIs. A recent study suggests that the administration of vaginal suppositories containing L. crispatus GAI 98332 is safe and effective in preventing rUTIs. Evidence show that L. rhamnosus Gr-1 and L. fermentum-RC can also colonize the vagina. However, clinical studies that determine the optimal dosage, duration and mode of lactobacilli delivery for establishing vaginal and/or periurethral colonization are still lacking [12]. 6. Cranberry in the prevention and treatment of UTIs Cranberry contains a proanthocyanidin that counteracts bladder colonization by E. coli by inhibiting the attachment of bacteria to the uroepithelial mucosa. Anti-inflammatory activity of cranberry extract prevents the development of symptoms but also to lower intercellular bacterial propagation, and thus reduces the frequency of UTIs and the propensity towards chronic infection. Evidence shows that consumption of cranberry juice significantly reduces clinical UTIs’ episodes in women with a history of UTIs in the previous year and antibiotic use for treatment of these events [13]. A more recent Cochrane review reports a nonsignificant reduction in risk of rUTIs with cranberry treatment and a study by Juthani-Mehta et al. supports the view that cranberry products should not be recommended as a medical intervention for the prevention of rUTIs [14]. In spite of these data, literature as well as expert opinion is still conflicting on the clinical role of cranberry to prevent UTIs. In the wake of conclusive data, cranberry remains a popular and safe approach in the management of UTIs. 7. d-Mannose and UTIs d-Mannose is a simple sugar, a monosaccharide, closely related to glucose. d-Mannose is rapidly absorbed and then excreted by the urinary tract. The bladder wall is coated with various mannosilate proteins, such as Tamm-Horsfall protein (THP) that interfere directly with the adhesion of bacteria on the mucosa. THP may fasten to E. coli with a specific bond, which may be inhibited by exogenous d-mannose. This provides the rationale for use of d-
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Fig. 1. Preventing urinary tract infections after menopause without antibiotics.
mannose in the treatment of UTIs, particularly determined by E. coli. Many studies, including that of Vicariotto et al. [15], show that hallmark symptoms of UTIs are significantly improved by d-mannose. Another study from Domenici and colleagues is confirmatory. Additional studies are needed to support and validate these preliminary results [16].
8. Newer concepts in the prevention and treatment of UTIs The oral immunostimulant, OM-89, is an extract of 18 different serotypes of heat killed uropathogenic E. coli, which stimulates innate immunity by increasing neutrophils and macrophage phagocytosis. OM-89 shows promise in the prevention of recurrent UTIs [17]. A similar concept is provided by the vaginal vaccine, Urovac: it contains 10 heat killed uropathogenic bacteria including 6 different serotypes of UPEC, and 1 strain each of Proteus vulgaris, Klebsiella pneumoniae, Morganella morganii and Enterococcus faecalis. This vaccine primarily induces humoral immunity in the urogenital tract [18]. A new therapy based on the reinstatement of the glycosaminoglycan (GAG) bladder epithelium has recently been proposed for the treatment of rUTIs. This GAG layer consists of non-sulfated, for example, hyaluronic acid (HA), and sulfated, for example, heparan sulfate and heparin, chondroitin sulfate (CS), GAG. Ciani et al. perform a European retrospective multicentre study to compare the clinical effectiveness of bladder instillations of GAG versus standard
management of rUTIs in adult women [19]. However, large-scale studies are needed to underline the benefit of this therapy.
9. Conclusions The use of vaginal estrogen, oral and vaginal probiotics, cranberry prophylaxis is backed up by growing evidence of efficacy. d-Mannose is also emerging as an effective treatment, although larger studies are needed to confirm its efficacy. Newer strategies including modern adherence inhibitors or immunologic interventions are needed to broaden the therapeutic portfolio in the hands of physicians (Fig. 1). Recurrent UTIs represent a common and distressing problem for ageing women. UTIs are also costly for the health care system. A wiser use of antimicrobial therapy is needed, particularly in elderly women. Hence, non-antibiotic therapies are important in this age group, and it is key to strengthen the evidence on the safety and efficacy of the available therapeutic strategies to path the way to improved efficacy and cost-effectiveness.
10. Practice points Recurrent urinary tract infections (rUTIs) are common in ageing women. The majority of recurrences are reinfection from extraurinary sources, such as the rectum or vagina. Vaginal estrogens reduce the incidence of UTIs. Probiotics, cranberry extracts and d-mannose are effective in reducing the risk of UTIs.
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11. Research agenda Further wide-scale randomized studies are needed to establish the role of estrogen therapy, probiotics and lactobacilli, as well as to identify other possible methods to reduce the use of antibiotics. Contributors All authors reviewed the literature, prepared and edited the manuscript. Conflict of interest The authors declare that they have no conflict of interest. Funding No funding was received for the preparation of this review. Provenance and peer review Peer review was directed by Prof. Margaret Rees independently of Tommaso Simoncini (one of the authors and an Editor of Maturitas), who was blinded to the process. References [1] D. Hickling, V. Nitti, Management of recurrent urinary tract infections in healthy adult women, Rev. Urol. 15 (2) (2013) 41–48. [2] Hyun-Kyung Kim, So-Yeon Kang, Youn-Jee Chung, Jang-Heub Kim, Mee-Ran Kim, The recent review of the genitourinary syndrome of menopause, J. Menopausal Med. 21 (2) (2015) 65–71. [3] R. Raz, Urinary tract infection in postmenopausal women. Review article, Korean J. Urol. 52 (12) (2011) 801–808. [4] M. Beerepoot, S. Geerlings, Non-antibiotic prophylaxis for urinary tract infections, Pathogens 5 (2) (2016) 36. [5] P. Mannella, G. Palla, M. Bellini, T. Simoncini, The female pelvic floor through midlife and aging, Maturitas 76 (2013) 230–234. [6] W.L. Pabich, S. Fihn, W. Stamm, D. Scholes, E.-J. Boyko, K. Gupta, Prevalence and determinants of vaginal flora alterations in postmenopausal women, J. Infect. Dis. 188 (7P) (2003) 1054–1058.
[7] R. Raz, R. Colodner, Y. Rohana, S. Battino, E. Rottensterich, I. Wasser, W. Stamm, Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women, Clin. Infect. Dis. 1 (36(11)) (2003) 1362–1368. [8] B. Eriksen, A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women, Am. J. Obstet. Gynecol. 180 (1999) 1072–1079. [9] E.C.M. Neves, M. Birkhauser, G. Samsioe, I. Lambrinoudaki, S. Palacios, R.S. Borrego, et al., EMAS position statement: the ten point guide to the integral management of menopausal health, Maturitas 81 (2015) 88–92. [10] S. Palacios, C. Castelo-Branco, H. Currie, et al., Update on management of genitourinary syndrome of menopause: a practical guide, Maturitas 82 (2015) 308–313. [11] W. Nseir, et al., The association between serum level of vitamin D and recurrent urinary tract infections in premenopausal women, Int. J. Infect. Dis. 2013 (2016) 1021–9712. [12] Shinya Ueharaa, Koichi Mondena, Koji Nomotob, Yuko Senoa, Reiko Kariyamaa, Hiromi Kumona A pilot study evaluating the safety and effectiveness of Lactobacillus vaginal suppositories in patients with recurrent urinary tract infection, Int. J. Antimicrob. Agents (2006) S30–S34. [13] Kevin C Maki, Kerrie L Kaspar, Christina Khoo, Linda H Derrig, Arianne L. Schild, Kalpana Gupta, Consumption of a cranberry juice beverage lowered the number of clinical urinary tract infection episodes in women with a recent history of urinary tract infection, Am. Soc. Nutr. 103 (6) (2016) 1434–1442. [14] E. Lindsay, Cranberry for prevention of urinary tract infection? Time to move on, JAMA 316 (November (18)) (2016) 1873–1874. [15] Vicariotto Effectiveness of an association of a cranberry dry extract, d-Mannose, and the two microorganisms Lactobacillus plantarum LP01 and Lactobacillus paracasei LPC09 in women affected by cystitis: a pilot study, J. Clin. Gastroenterol. 48 (November–December, Suppl. 1) (2014) S96–101. [16] L. Domenici, M. Monti, C. Bracchi, M. Giorgini, V. Colagiovanni, L. Muzii, P. Benedetti Panici, d-Mannose: a promising support for acute urinary tract infections in women. A pilot study, Eur. Rev. Med. Pharmacol. Sci. 20 (2016) 2920–2925. [17] M. Huber, K. Krauter, G. Winkelmann, H.W. Bauer, V.W. Rahlfs, P.A. Lauener, G.S. Blessmann, W.G. Bessler, Immunostimulation by bacterial components: II. Efficacy studies and meta-analysis of the bacterial extract OM-89, Int. J. Immunopharmacol. 22 (2000) 1103. [18] W.J. Hopkins, J. Elkahwaji, L.M. Beierle, G.E. Leverson, D.T. Uehling, Vaginal mucosal vaccine for recurrent urinary tract infections in women: results of a phase 2 clinical trial, J. Urol. 177 (2007) 134. [19] O. Ciani, E. Arendsen, M. Romancik, R. Lunik, E. Costantini, M. Di Biase, G. Morgia, E. Fragalà, T. Roman, M. Bernat, G. Guazzoni, R. Tarricone, M. Lazzeri, Intravesical administration of combined hyaluronic acid (HA) and chondroitin sulfate (CS) for the treatment of female recurrent urinary tract infections: a European multicentre nested case-control study, BMJ 6 (March (3)) (2016).