Urogenital Infections and Inflammations

T.E. Bjerklund Johansen, F. M.E. Wagenlehner, Y.-H. Cho, T. Matsumoto, J. N. Krieger, D. Shoskes, K. Naber

Asymptomatic bacteriuria in recurrent UTI – to treat or not to treat

 Tommaso Cai 1
Riccardo Bartoletti 2


1 Dept. of Urology, Santa Chiara Regional Hospital, Trento, Italy
2 Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy

Abstract

Asymptomatic bacteriuria (ABU) is a common clinical condition that often leads to unnecessary antimicrobial use. The reduction of antibiotic overuse for ABU is consequently an important issue for antimicrobial stewardship to reduce the emergence of multidrug resistant strains. In the clinical setting we have an important issue that requires special attention: the role of ABU in women affected by recurrent urinary tract infections (rUTIs). In everyday clinical practice, young women affected by rUTI show after antibiotic treatment asymptomatic periods associated sometimes with or without bacteriuria. Although it is not recommended, the majority of women with ABU is treated with poor results and occasionally a selection of multidrug-resistant bacteria can be observed. Recent studies demonstrated that ABU should not be treated in young women affected by rUTI, because it may play even a protective role in preventing symptomatic episodes, particularly when Enterococcus faecalis has been isolated. Moreover, ABU treatment is associated with a higher occurrence of antibiotic-resistant bacteria, indicating that ABU treatment in women with rUTIs is even potentially dangerous.


Summary of recommendations

  1. Asymptomatic bacteriuria (ABU) is a bacterial colonization, but not  an infection that requires treatment.
  2. ABU is generally common in women affected by recurrent UTIs, specially after antibiotic treatment.
  3. ABU has a protective role in preventing symptomatic recurrences, particularly when Enterococcus faecalis has been isolated.
  4. ABU treatment is associated with a higher occurrence of antibiotic-resistant bacteria.
  5. ABU treatment in women with rUTIs is therefore potentially dangerous.

Introduction

This review addresses the role and management of asymptomatic bacteriuria (ABU) in women affected particularly by recurrent urinary tract infections (rUTI). ABU in pregnant women, in men, in children, after transplantation, before urological surgery etc. are not addressed in this review.

Methods

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 ABU [1], [2]. Moreover, a systematic literature search was performed in Medline, Cochrane, and Embase. The following keywords have been used: asymptomatic bacteriuria and recurrent urinary tract infection. The limitations included adult with age over 18 years, clinical studies, English and peer reviewed. A total of 161 publications were identified and screened by title and abstract. All publications about pregnancy, transplantation, prophylaxis, and children were excluded. Finally, 14 papers were included in this review. The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using ICUD standards [3].

Definition, context and clinical application

Microbiological definition

An episode of ABU was defined as the presence of at least 105 Colony Forming Unit (CFU) of uropathogenic bacteria per milliliter in two consecutive voided urine specimens of a midstream urine specimen obtained from an asymptomatic woman on a routine scheduled visit [1].

Clinical setting

ABU is a bacterial colonization that does not indicate an infection and is generally present in 3% to 5% of young women [4], [5]. Although ABU is more common in patients with diabetes mellitus and elderly persons, its treatment is generally recommended only in pregnant women and at the pre-operative evaluation before surgical procedures [1], [2], [5]. Regardless of these recommendations, overuse of antibiotics in ABU treatment is common. In fact, about one-third of ABU were over-treated contrary to the guidelines, with important negative consequences on public health [6], [7], [8]. In everyday clinical practice, young sexually active women affected by rUTI show, after antibiotic treatment, an asymptomatic period associated sometimes with or without bacteriuria [9]. Although it is not recommended, the majority of women with ABU is treated with poor results and with a high risk of selecting multidrug resistance pathogens [10]. Recently, Cai et al. even demonstrated a protective effect of spontaneously developed ABU in women with rUTIs without other associated risk factors [9]. However, some authors stated that occasionally the eradication of a strain considered the causative agent of recurrent episodes of UTI may be justified [11]. Against this background, the question arises: What is the role of ABU treatment in women with rUTI?

What is the role of ABU treatment in women with recurrent urinary tract infections?

Recently, Cai et al. showed, in a randomized clinical trial and in a prospective cohort study, four  important findings [9]:

  1. treatment of ABU is associated with a higher probability to develop symptomatic recurrence rate;
  2. treatment of ABU is associated with a modification of the isolated bacterial strains;
  3. the presence of ABU in patients affected by rUTI, without any associated risk factor, has a protective role in development of subsequent symptomatic UTI, particularly when Enterococcus faecalis has been found;
  4. treatment of ABU is associated with a higher prevalence of antibiotic-resistant bacteria [10].

The change in isolated bacteria from the urinary tract after antibiotic therapy is well known and known to be dangerous in several cases. Beerepoot et al. demonstrated that oral administration of low dose antibiotics for the prevention of UTIs could cause ecological disturbances in normal intestinal microflora, while promoting the emergence of antimicrobial-resistant strains [12]. Moreover, several authors demonstrated that antibiotic therapy is able to disturb the ecological balance in the colon tract and to suppress the normal microflora [12], [13]. The ecological effects of antibacterial agents on the human microflora should be the main reason of the negative effect of antibiotic therapy in women affected by rUTIs with ABU. The normal bacterial intestinal flora represents an extremely important defense mechanism, which effectively interferes with the establishment of many important enteric pathogens [14]. It is well known that mechanisms by which microorganisms suppress the growth of other microorganisms include modification of bile acids, stimulation of peristalsis, induction of immunologic responses, depletion of essential substrates from the environment, competition for attachment sites, creation of restrictive physiologic environments, and elaboration of antibiotic-like substances [13], [14]. For example, it has been demonstrated that normal bacterial intestinal flora is able to stimulate the production of secretory IgA, an antibody class unique to the mucosae [15]. In this sense, the presence of IgA in the intestinal lumen should be considered a primitive front line defense against induction of autoimmunity and invasion by microbial pathogens [16]. Components of the intestinal microbial flora also interact synergistically in the induction of disease or the utilization of substrate. In this sense, we can hypothesize that E. faecalis should be an extremely important defense mechanism, which effectively interferes with the establishment of many important enteric pathogens, such as E. coli [9], [10]. Finally, in two randomized controlled trials on the prevention of recurrent UTI in non-hospitalized premenopausal and postmenopausal women [Non-antibiotic prophylaxis for recurrent urinary tract infections’ (NAPRUTI) study], Beerepoot and co-workers found that the predictive values of the susceptibility pattern of the ABU strain, based on resistance prevalence at baseline, were 76%, except in the case of nitrofurantoin and amoxicillin-clavulanic acid-resistance [17]. Moreover, they found that the susceptibility pattern of E. coli strains isolated during the month before a symptomatic E. coli UTI can be used to make informed choices for empirical antibiotic treatment in this patient population [17].

Role of ABU in older women with recurrent UTI

It is well known that the incidence of ABU increases from 3.5% in the general population to 16% to 18% in women older than 70 years and some longitudinal studies report that it affects 50% of older women [18]. In one longitudinal prospective series of ambulatory older adults, patterns of bacteriuria observed in urine samples obtained at 6-month intervals revealed that more than 30% of patients had spontaneously resolving bacteriuria and another 30% who initially did not have bacteriuria subsequently developed it [18], [19]. On the other hand, even if UTI in older women can be a serious problem, due to the risk of upper urinary tract infections, several randomized controlled trials found that 25% to 50% of women presenting with UTI symptoms will have recovered in 1 week without using antibiotics [20], [21]. In this sense, delaying antibiotic treatment while evaluating a symptomatic UTI generally does not lead to adverse outcomes [18].

Most authors therefore suggest to delay antibiotic treatment while conducting further evaluation when the diagnosis of symptomatic UTI is in doubt in older women and offer supportive treatment such as increased fluid intake. In fact, spontaneous symptom improvement occurs in 50% of community-dwelling non-catheterized women who delay antibiotic treatment [22], [23]. Moreover, in 1994, Abrutyn and co-workers demonstrated that reinfection rates (1.67 vs 0.87 per patient-year of follow-up), adverse antimicrobial drug effects, and isolation of increasingly resistant organisms occur more commonly in ABU therapy vs non-therapy groups [24].

Conclusions

Evaluation of the role of ABU in women affected by rUTIs is a key point in order to optimize antibiotic usage and to prevent an increased rate of resistant bacteria. In line with the latest studies, all physicians should be aware of  these findings and avoid antibiotic treatment of ABU in women with rUTI.

Note

This chapter was primarily published in the journal GMS Infectious Diseases [25].


References

[1] Grabe M, Bartoletti R, Bjerklund Johansen TE, Cai T, Çek M, Köves B, Naber KG, Pickard RS, Tenke P, Wagenlehner F, Wullt B. Guidelines on Urological Inections. European Association of Urology; 2015. Available from: http://uroweb.org/wp-content/uploads/19-Urological-infections_LR2.pdf
[2] Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM; Infectious Diseases Society of America; American Society of Nephrology; American Geriatric Society. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005 Mar;40(5):643-54. DOI: 10.1086/427507
[3] Abrams P, Khoury S, Grant A. Evidence-based medicine overview of the main steps for developing and grading guideline recommendations. Prog Urol. 2007;17(3):681-4. DOI: 10.1016/S1166-7087(07)92383-0
[4] Hooton TM, Scholes D, Stapleton AE, Roberts PL, Winter C, Gupta K, Samadpour M, Stamm WE. A prospective study of asymptomatic bacteriuria in sexually active young women. N Engl J Med. 2000 Oct;343(14):992-7. DOI: 10.1056/NEJM200010053431402
[5] Raz R. Asymptomatic bacteriuria. Clinical significance and management. Int J Antimicrob Agents. 2003 Oct;22 Suppl 2:45-7. DOI: 10.1016/S0924-8579(03)00248-6
[6] Lee MJ, Kim M, Kim NH, Kim CJ, Song KH, Choe PG, Park WB, Bang JH, Kim ES, Park SW, Kim NJ, Oh MD, Kim HB. Why is asymptomatic bacteriuria overtreated?: A tertiary care institutional survey of resident physicians. BMC Infect Dis. 2015 Jul 26;15:289. DOI: 10.1186/s12879-015-1044-3
[7] Cai T, Verze P, Brugnolli A, Tiscione D, Luciani LG, Eccher C, Lanzafame P, Malossini G, Wagenlehner FM, Mirone V, Bjerklund Johansen TE, Pickard R, Bartoletti R. Adherence to European Association of Urology Guidelines on Prophylactic Antibiotics: An Important Step in Antimicrobial Stewardship. Eur Urol. 2016 Feb;69(2):276-83. DOI: 10.1016/j.eururo.2015.05.010
[8] Wagenlehner FM, Bartoletti R, Cek M, Grabe M, Kahlmeter G, Pickard R, Bjerklund-Johansen TE. Antibiotic stewardship: a call for action by the urologic community. Eur Urol. 2013 Sep;64(3):358-60. DOI: 10.1016/j.eururo.2013.05.044
[9] Cai T, Mazzoli S, Mondaini N, Meacci F, Nesi G, D'Elia C, Malossini G, Boddi V, Bartoletti R. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? Clin Infect Dis. 2012 Sep;55(6):771-7. DOI: 10.1093/cid/cis534
[10] Cai T, Nesi G, Mazzoli S, Meacci F, Lanzafame P, Caciagli P, Mereu L, Tateo S, Malossini G, Selli C, Bartoletti R. Asymptomatic bacteriuria treatment is associated with a higher prevalence of antibiotic resistant strains in women with urinary tract infections. Clin Infect Dis. 2015 Dec;61(11):1655-61. DOI: 10.1093/cid/civ696
[11] Grabe M, Bartoletti R, Bjerklund-Johansen TE, Çek HM, Pickard RS, Tenke P, Wagenlehner F, Wullt B. Guidelines on Urological Infections. European Association of Urology; 2014. Available from: http://uroweb.org/wp-content/uploads/19-Urologicalinfections_LR.pdf
[12] Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke TM, Prins JM, Koeijers J, Verbon A, Stobberingh E, Geerlings SE. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Intern Med. 2011 Jul 25;171(14):1270-8. DOI: 10.1001/archinternmed.2011.306
[13] Edlund C, Nord CE. Effect on the human normal microflora of oral antibiotics for treatment of urinary tract infections. J Antimicrob Chemother. 2000 Aug;46 Suppl A:41-8. DOI: 10.1093/jac/46.suppl_1.41
[14] Rolfe RD. Interactions among microorganisms of the indigenous intestinal flora and their influence on the host. Rev Infect Dis. 1984 Mar-Apr;6 Suppl 1:S73-9. DOI: 10.1093/clinids/6.Supplement_1.S73
[15] Wijburg OL, Uren TK, Simpfendorfer K, Johansen FE, Brandtzaeg P, Strugnell RA. Innate secretory antibodies protect against natural Salmonella typhimurium infection. J Exp Med. 2006 Jan 23;203(1):21-6. DOI: 10.1084/jem.20052093
[16] Bouvet JP, Dighiero G. From natural polyreactive autoantibodies to à la carte monoreactive antibodies to infectious agents: is it a small world after all? Infect Immun. 1998 Jan;66(1):1-4.
[17] Beerepoot MA, den Heijer CD, Penders J, Prins JM, Stobberingh EE, Geerlings SE. Predictive value of Escherichia coli susceptibility in strains causing asymptomatic bacteriuria for women with recurrent symptomatic urinary tract infections receiving prophylaxis. Clin Microbiol Infect. 2012 Apr;18(4):E84-90. DOI: 10.1111/j.1469-0691.2012.03773.x
[18] Mody L, Juthani-Mehta M. Urinary tract infections in older women: a clinical review. JAMA. 2014 Feb;311(8):844-54. DOI: 10.1001/jama.2014.303
[19] Kaye D, Boscia JA, Abrutyn E, Levison ME. Asymptomatic bacteriuria in the elderly. Trans Am Clin Climatol Assoc. 1989;100:155-62.
[20] Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract. 2002 Sep;52(482):729-34.
[21] Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J Prim Health Care. 2007 Mar;25(1):49-57. DOI: 10.1080/02813430601183074
[22] Knottnerus BJ, Geerlings SE, Moll van Charante EP, ter Riet G. Women with symptoms of uncomplicated urinary tract infection are often willing to delay antibiotic treatment: a prospective cohort study. BMC Fam Pract. 2013 May 31;14:71. DOI: 10.1186/1471-2296-14-71
[23] Elstad EA, Maserejian NN, McKinlay JB, Tennstedt SL. Fluid manipulation among individuals with lower urinary tract symptoms: a mixed methods study. J Clin Nurs. 2011 Jan;20(1-2):156-65. DOI: 10.1111/j.1365-2702.2010.03493.x
[24] Abrutyn E, Mossey J, Berlin JA, Boscia J, Levison M, Pitsakis P, Kaye D. Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women? Ann Intern Med. 1994 May;120(10):827-33. DOI: 10.7326/0003-4819-120-10-199405150-00003
[25] Cai T, Bartoletti R. Asymptomatic bacteriuria in recurrent UTI – to treat or not to treat. GMS Infect Dis. 2017;5:Doc09. DOI: 10.3205/id000035

The ZB MED – Information Center for Life Sciences, Germany, together with the European Association of Urology (EAU) provided the opportunity to publish a “Living Textbook” on “Urogenital Infections and Inflammations” in an open access form. This “Living Textbook” represents also an update of the Textbook on Urogenital Infections published 2010 by the International Consultation on Urological Infections and the EAU: http://www.icud.info/urogenitalinfections.html.

The “Living Textbook” will cover infections and inflammations of the kidney, the urinary tract, as well as the male and female genital tract considering pathogenesis, diagnostics, treatment, prophylaxis and future aspects. The “Living Textbook” will be structured into about 26 Sections each with two section co-chairs responsible for peer review of the chapters of each section. Each chapter should reflect the background to the topic and highlight all of the critical evidence relating to the subject. The intention is to provide an up to date, concise synthesis of the literature on that topic, and for clinical topics also recommendations based on levels of evidence for contemporary clinical practice, as well as suggested research recommendations.

The editors hope that this “Living Textbook” may become a useful instrument for physicians of different specialties taking care about patients suffering from these diseases.

Truls E. Bjerklund Johansen (Norway),

Florian ME Wagenlehner (Germany),

Yong-Hyun Cho (South Korea),

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John N Krieger (USA),

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  1. Abstract
  2. Summary of recommendations*/key notes*
    (*which ever term is more appropriate)
  3. Introduction
  4. Methods
  5. Results
  6. Further research
  7. Conclusions
  8. Acknowledgement
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Alternatively, absence of high level evidence does not necessarily preclude a grade A recommendation, if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where corroborating studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal recommendations are considered helpful for the reader. The quality of the underlying scientific evidence - although a very important factor – has to be balanced against benefits and burdens, values and preferences and costs when a grade is assigned.

Since the same rating system should be used in all chapters, for the sake of brevity the same sentence could be used in “Methods” for all manuscripts, because the rating system will be described in details in the Preface of the book:

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References

[1] European Association of Urology. Guidelines. Methodology section. 2015 ed. Arnhem: European Association of Urology; 2015. p. 3. ISBN/EAN: 978-90-79754-80-9. Available from: http://uroweb.org/wp-content/uploads/EAU-Extended-Guidelines-2015-Edn..pdf

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University of Washington Section of Urology

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Cleveland Clinic Glickman Urological and Kidney Institute

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St. Mary's Hospital, The Catholic University of Korea Department of Urology

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University of Occupational and Environmental Health Department of Urology

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Justus-Liebig University of Giessen Clinic of Urology and Andrology

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Oslo University Hospital Urology Department

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Technical University of Munich

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University of Pisa
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Oslo University Hospital
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University Basel
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Queen's University
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Rostov Medical State University
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Hyogo College of Medicine
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Chung-Ang University
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University of Washington
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Novosibirsk Research TB Institute, Novosibirsk State Medical University

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Feinberg School of Medicine, Northwestern University
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Technical University of Munich

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The University of Queensland
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Klinikum Memmingen
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Des Moines University Medical College of Ostheopathic Medicine

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Cleveland Clinic
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Prof. Dr. Roswitha Siener

University of Bonn
University Stone Centre, Department of Urology

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Sofia Sjöström

Queen Silvia Childrens Hospital, Sahlgrens Academy
Pediatric surgery and urology

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Mathew Sorensen

University of Washington School of Medicine
Department of Urology

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Prof. Dr. Dr. Walter Ludwig Strohmaier FEBU

Regiomed-Klinikum Coburg. Medical School Regiomed
Urology and Paediatric Urology

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Satoshi Takahashi

Sapporo Medical University School of Medicine
Department of Infection Control and Laboratory Medicine

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Professor Paul Anantharajah Tambyah

Yong Loo Lin School of Medicine, National University Hospital
Department of Medicine

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Peter Tenke

South-Pest Hospital
Department of Urology

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Praveen Thumbikat


Department of Urology

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Dr. Jose Tiran Saucedo

IMIGO / Universidad de Monterrey
Obstetrics and Gynaecology

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Dominic Tran-Nguyen

Des Moines University

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Dean Tripp

Queen's University
Psychology, Anesthesia & Urology

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Prof. SEONGHEON WIE

The Catholic University of Korea, St. Vincent's Hospital
Division of Infectious Diseases, Department of Internal Medicine

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Florian M. E. Wagenlehner MD, PhD

Justus-Liebig University of Giessen
Clinic of Urology and Andrology

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Assoc. Prof. Christian Wejse

Aarhus University, Aarhus University Hospital
Department of Infectious Diseases/Center for Global Health, Dept of Public Health

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Prof. Dr. Mete Çek

Trakya University, School of Medicine
Urology

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