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Review

Urol Int Received: October 2, 2017 Accepted after revision: December 7, 2017 Published online: January 17, 2018

Internationalis Urologia

Prof. Dr. med. Florian M. Wagenlehner Clinic of Urology, Pediatric Urology and Andrology Justus Liebig University DE–35392 Giessen (Germany) E-Mail Florian.Wagenlehner @ chiru.med.uni-giessen.de

© 2018 S. Karger AG, Basel

E-Mail [email protected] www.karger.com/uin

DOI: 10.1159/000486138

Keywords Urinary tract infection · Cystitis · Pyelonephritis · Diagnosis · Systematic review · Clinical guideline

Abstract Objectives: We aimed to update the 2010 evidence- and consensus-based national clinical guideline on the diagnosis and management of uncomplicated urinary tract infections (UTIs) in adult patients. Materials and Methods: An interdis- ciplinary group consisting of 17 representatives of 12 medi- cal societies and a patient representative was formed. Sys- tematic literature searches were conducted in MEDLINE, EMBASE, and the Cochrane Library to identify literature pub- lished in 2010–2015. Results: We provide 75 recommenda-

tions and 68 statements in the updated evidence- and con- sensus-based national clinical guideline. The diagnostics part covers practical recommendations on cystitis and py- elonephritis for each defined patient group. Clinical exami- nations, as well as laboratory testing and microbiological pathogen assessment, are addressed. Conclusion: In accor- dance with the global antibiotic stewardship initiative and considering new insights in scientific research, we updated our German clinical UTI guideline to promote a responsible antibiotic use and to give clear hands-on recommendations for the diagnosis and management of UTIs in adults in Ger- many for healthcare providers and patients.

© 2018 S. Karger AG, Basel

a St.-Antonius-Hospital, Department

of Urology and Paediatric Urology, Eschweiler, Germany; b UroEvidence@ Deutsche Gesellschaft für Urologie, Berlin, Germany; c Pharmacy, Klinikum Nürnberg, Nürnberg, Germany; d Klinik für Innere Medizin C, Hämatologie/Onkologie, Universitätsmedizin Greifswald, Greifswald, Germany; e Department of Obstetrics and Gynecology, Medical Center- University of Freiburg, Freiburg, Germany; f Department of Infectious Diseases, Laboratory Dr. Wisplinghoff, Cologne, Germany; g

Department in Division of Infectious Diseases, University Hospital Carl Gustav Carus, TU Dresden, Germany; h Department of Urologie, Kurpark-Klinik, Bad Nauheim, Germany; i Technical University of Munich, Munich, Germany; j Institute for Public Health and Nursing Science, Department for Health Services Research, Bremen University, Bremen, Germany; k Clinic of Urology, Pediatric Urology and Andrology, Justus Liebig University, Giessen, Germany

The 2017 Update of the German Clinical Guideline on Epidemiology, Diagnostics, Therapy, Prevention, and Management of Uncomplicated Urinary Tract Infections in Adult Patients: Part 1

Jennifer Kranz a, b Stefanie Schmidt b Cordula Lebert c Laila Schneidewind b, d Falitsa Mandraka e Mirjam Kunze f Sina Helbig g Winfried Vahlensieck h Kurt Naber i Guido Schmiemann j Florian M. Wagenlehner k

J.K. and S.S. contributed equally to this study.

Kranz et al.Urol Int2 DOI: 10.1159/000486138

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Background

Uncomplicated, bacterial, community-acquired uri- nary tract infections (UTIs), including cystitis and pyelo- nephritis, are among the most common infections in the outpatient setting. Data on antibiotic consumption in un- complicated UTIs from the German Barmer health insur- ance, one of the largest health insurance funds, on pre- scribing practice in the treatment of cystitis are in sharp contrast to the recommendations of the German clinical guideline on uncomplicated UTIs of 2010 [1] not to use fluoroquinolones in uncomplicated cystitis. In contrast to the guideline recommendations, primarily fluoroquino- lones (48%) were prescribed [2].

Antibiotic resistance is a growing global problem that leads to significant challenges and costs in the health care system [1–5]. The resistance level of pathogens against commonly used antibiotics of uncomplicated UTIs has sig- nificantly increased in recent years. Recognition of this fact has led to an international re-evaluation of therapeutic rec- ommendations in uncomplicated UTIs [4]. In accordance with this global initiative and the achievements in the an- tibiotic stewardship movement, we updated our German clinical UTI guideline to promote a responsible antibiotic use in the management of UTIs in adults in Germany.

The German Society for Urology (DGU) was heading the update process of the interdisciplinary Association of Scientific Medical Societies in Germany S3 guideline. Funding by the pharmaceutical industry was strictly avoided; the conflicts of interest by the members of the guideline group were disclosed and discussed openly. The German Association of Scientific Medical Societies in Germany (AWMF) S3 guideline is free for download available in a short and long version on the website of the AWMF (http://www.awmf.org/leitlinien/detail/ll/043– 044.html) [6]. The category S3 refers to the German guide- line classification form, where S3 represents the highest methodological standard and involves both evidence- and consensus-based concepts to achieve guideline recom- mendations from an interdisciplinary panel group [7].

The guideline recommendations address all medical specialties involved in the diagnostics, therapy, manage- ment, and prevention of acute uncomplicated UTIs (Ta- ble 1), for example, general practitioners, gynecologists, infectious disease specialists, microbiologists, nephrolo- gists, urologists, and laboratory physicians.

Here, we present the main content of the updated guideline in 2 parts. Part I focuses on the recommenda- tions regarding the definition of patient groups and the diagnostics of uncomplicated bacterial UTI acquired in

the outpatient setting in adult patients. Part II will cover the treatment of acute episodes of cystitis and pyelone- phritis and prophylaxis of recurrent UTIs.

Objective

The objective of the study was to update the 2010 evi- dence- and consensus-based national guideline on the di- agnostics and management of uncomplicated UTIs in adult patients. Specific objectives were (a) to promote a rational use of antimicrobial substances, (b) to avoid an inappropri- ate use of antibiotic therapies (i.e., use without indication), and (c) to avoid the development of antibiotic resistances.

Methods

The AWMF S3 clinical guideline is based on an interdisciplin- ary consensus group consisting of 17 representatives of 12 medical societies and a member of a patient organization, thus considering all relevant medical specialties involved in the diagnostics and the management of UTIs in adult patients (Table 1).

A systematic literature search was conducted in the databases MEDLINE, EMBASE, and the Cochrane Library to identify the lit- erature published between January 2010 and December 2015. Inter- national clinical guidelines, systematic reviews, meta-analysis, and randomized clinical trials on this topic were considered for inclu- sion. For specific chapters, like epidemiology, collateral damage, or diabetic patients with UTI, individual searches were conducted and the experts selected specific literature outside the above-mentioned inclusion criteria. The literature searches identified 2,909 publica- tions, which were screened for inclusion. Finally, 156 publications (primary and secondary studies as well as clinical guidelines) were considered as relevant. The risk of bias of the included studies was assessed using AGREE [8], AMSTAR [9], or the Cochrane tool for randomized clinical trials [10]. The Oxford criteria were used for the level of evidence ratings (Table 2) [11]. A formal consensus was achieved through the nominal group process under the guidance of an external moderator from the AWMF with the representatives of the participating medical associations. The evidence-based recom- mendations were developed in a consensus conference.

The following 3 grades of recommendations were categorized: • A: strong recommendation: should/should not (German: “soll”) • B: recommendation: ought to/ought not to (German “sollte”) • C: open recommendation: may be considered

The process of development of the S3 Guideline is illustrated in Figure 1.

Definition of UTIs

A UTI is classified as uncomplicated if there are no relevant functional or anatomical anomalies in the uri- nary tract, no relevant renal functional impairment and

Clinical Practice Guideline: Uncomplicated UTIs

3Urol Int DOI: 10.1159/000486138

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Table 1. Participating medical societies and working groups

Medical Society or working group Participants in the update 2017

German Society of Urology (DGU, Deutsche Gesellschaft für Urologie) – lead organization Dr. J. Kranz Prof. Dr. K.G. Naber Dr. S. Schmidt Dr. L. Schneidewind Priv. Doz. Dr. W. Vahlensieck Prof. Dr. F.M.E. Wagenlehner

German Society for General and Family Medicine (DEGAM, Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin)

Prof. Dr. E. Hummers Priv. Doz. Dr. G. Schiemann

German Society of Gynecology and Obstetrics (DGGG, Deutsche Gesellschaft für Gynäkologie und Geburtshilfe)

Prof. Dr. U. Hoyme Dr. M. Kunze

German Society for Hygiene and Microbiologie (DGHM, Deutsche Gesellschaft für Hygiene und Mikrobiologie)

Dr. E. Kniehl

German Society of Infectious Diseases (DGI, Deutsche Gesellschaft für Infektiologie) Dr. S. Helbig Dr. F. Mandraka

German Society of Nephrology (DGfN, Deutsche Gesellschaft für Nephrologie) Prof. Dr. R. Fünfstück Prof. Dr. U. Sester

Paul Ehrlich Society for Chemotherapy (PEG, Paul-Ehrlich-Gesellschaft für Chemotherapie) Prof. Dr. R. Fünfstück Dr. E. Kniehl Prof. Dr. K.G. Naber Prof. Dr. F.M.E. Wagenlehner

Deutsche Gesellschaft für Klinische Chemie und Laboratoriumsmedizin (DGKL) Prof. Dr. W. Hofmann

Bundesverband Deutscher Krankenhausapotheker (AKDA) Dr. C. Lebert

CA-Deutschland e.V., Förderverein Interstitielle Zystitis (patient representative) B. Mündner-Hensen

Table 2. Level of evidence after Oxford 2009 classification system [11]

Level of evidence

Diagnostics Therapy

Ia Systematic review (SR; with homogeneity) of level 1 diagnostic studies; clinical decision rule with 1b studies from different clinical centres

SR (with homogeneity) of randomized controlled studies (RCT)

Ib Validating cohort study with good reference standards, or clinical decision rule tested within 1 clinical centre

Individual RCT (with narrow confidence interval)

Ic Absolute SpPins* and SnNouts* All or none principle

IIa SR (with homogeneity) of level >2 diagnostic studies SR (with homogeneity) of cohort studies

IIb Exploratory cohort study with good reference standards, clinical decision rule after derivation, or validated only on split-sample or databases

Individual cohort study (including low quality RCT)

IIc Outcomes research, ecological studies

IIIa SR (with homogeneity) of 3b and better studies SR (with homogeneity) of case-control studies

IIIb Non-consecutive study, or without consistently applied reference standards

Individual case-control study

IV Case-control study, poor or non-independent reference standard

Case-series (and poor-quality cohort and case-control studies)

V Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles

Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles

* An “Absolute SpPin” is a diagnostic finding whose specificity is so high that a positive result rules-in the diagnosis. An “Absolute SnNout” is a diagnostic finding whose sensitivity is so high that a negative result rules-out the diagnosis [11].

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no relevant concomitant disease that would promote the UTI, or the risk of developing serious complications [3]. • Acute uncomplicated cystitis: A lower UTI (cystitis) is

assumed when the acute symptoms refer only to the lower urinary tract, for example, urgency, pain on mic- turition (dysuria), pollakisuria, and pain above the symphysis.

• Acute uncomplicated pyelonephritis: An upper UTI (pyelonephritis) ought to be assumed if, in the case of acute symptoms, flank pain, pain on palpation of the flank, and/or fever (>38  ° C) persist.

• Asymptomatic bacteriuria: Clinically symptomatic UTI is distinguished from asymptomatic bacteri- uria. The term ‘asymptomatic UTI’ ought not to be used.

• Recurrent uncomplicated UTIs: A recurrent UTI is as- sumed if relapse rates of ≥2 symptomatic episodes oc- cur within 6 months or ≥3 symptomatic episodes with- in 12 months.

Definition of Patient Groups

The following patient groups with uncomplicated UTI ought to be distinguished for diagnostic and therapeutic purposes: • Otherwise healthy, non-pregnant premenopausal

women (reference group). • Otherwise healthy pregnant women. • Otherwise healthy postmenopausal women. • Men with uncomplicated UTI. • Patients with diabetes mellitus.

Diagnostics

Diagnostic methods are designed to detect the pres- ence of UTIs, but also, when appropriate, to ascertain the etiology (bacterial spectrum) that triggered the infection and how it can be treated (susceptibility to antibiotics).

Clinical Examination As type and frequency of anatomical or symptomatic

complications may differ in individual patient groups, group-specific diagnostic strategies ought to be applied (V).

Women with suspected uncomplicated UTIs should be asked if they:

1. Have relevant pain on micturition and urgency 2. Suspect a UTI as a cause themselves 3. Have vaginal discomfort. If the answer to question 1 and/or 2 is “yes,” a UTI is

very likely. For vaginal complaints, a differential diagno- sis should also be considered (A, Ia).

Alternative diagnoses and gynecological examination ought to be considered in women who suffer from vaginal itching or vaginal discharge (B, Ia): the presence of pain on micturition, urgency, and occasional hematuria increases the likelihood of a UTI. If one or more of these symptoms are present, a positive dipstick (nitrite or leukocyte ester- ase alone or in combination) further increases the likeli- hood of a UTI (Ia). Diagnosis without direct patient con- tact is possible and has been successfully evaluated in some studies on telephone management or using an interactive computer response system. While this approach proved to be feasible in terms of patient satisfaction and cure rates,

Constitution and invitation of representative and interdisciplinary guideline panel group

Literature searches: systematic searches and selective literature inclusion for specific topics

Literature screening and quality appraisal

Guideline content review and content update based on current evidence

Review and update of statements and recommendations

Finding a panel group consens

External guideline review

Final guideline publication

Fig. 1. Steps in the development of the guideline.

Clinical Practice Guideline: Uncomplicated UTIs

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most of the studies used a retrospective design and did not assess diagnostic accuracy. The value of a non-personal doctor-patient treatment (telemedicine) has not been in- vestigated in Germany. Experiences with telemedicine from other countries cannot directly be transferred to the German healthcare system (Ib).

Diagnostics in Different Patient Groups In the following, specific recommendations for the di-

agnosis in non-pregnant premenopausal women without other relevant concomitant diseases are presented (stan- dard group). For the other patient groups, the specific recommendations on diagnosis are listed in the guideline document (http://www.awmf.org/leitlinien/detail/ll/043- 044.html).

Diagnosis of Acute Uncomplicated Cystitis in Non-Pregnant Premenopausal Women If women who have no risk factors for complicated

UTIs complain of typical symptoms (pain on micturition, pollakisuria, urgency), have no vaginal symptoms (itch- ing, altered discharge), have no fever and no flank pain, the presence of an uncomplicated cystitis may be consid- ered with high probability (IIa).

In the first manifestation of an acute UTI or, if the pa- tient is unknown to the doctor, a symptom-related medi- cal examination with clinical examination ought to be performed (B, V). The diagnosis of uncomplicated cysti- tis based on clinical criteria may be considered with high probability (sensitivity of 94.7%, specificity of 82.4%) with the use of the validated questionnaire (Acute Cystitis Symptom Score [ACSS]) [12], which assesses the severity of the symptoms and the course of the disease (IIb). The validated questionnaire ACSS may be considered to fol- low the course of cystitis over time and the effect of ther- apy (IIb) [13]. The ACSS questionnaire is translated and validated in several languages (www.acss.world).

In women with uncomplicated, non-recurrent or -re- fractory cystitis, with clear clinical symptoms, no micro- biological examination is recommended (IIIc). In symp- tomatic women, the detection of Escherichia coli in the midstream urine, independent of the number of patho- gens, is predictive for a bacterial UTI. In contrast, the de- tection of Enterococci and group B Streptococci in the midstream urine is not predictive for a UTI (Ib).

Diagnosis of Uncomplicated Acute Pyelonephritis in Non-Pregnant Premenopausal Women In the diagnosis of uncomplicated acute pyelonephri-

tis in non-pregnant women without other relevant con-

comitant diseases, the clinical examination follows the general principles (see above). In addition, a physical ex- amination and urine examination including a urine cul- ture should be carried out (A, V). In the diagnosis of un- complicated acute pyelonephritis in non-pregnant wom- en without other relevant concomitant diseases, further examinations (e.g., sonography) should be performed to exclude complicated factors (A, V).

Diagnosis of Asymptomatic Bacteriuria in Non-Pregnant Premenopausal Women In non-pregnant women without other relevant con-

comitant diseases, screening for asymptomatic bacteri- uria ought not to be carried out (A, Ia).

Diagnosis of Persistent and Recurrent UTIs in Non-Pregnant Premenopausal Women In patients with persistent hematuria or persistent de-

tection of pathogens other than E. coli, further studies such as urethrocystoscopy and further imaging ought to be performed (B, V). In patients with recurrent UTIs, a urine culture and a single sonography ought to be per- formed. Further invasive diagnostics ought not to be per- formed (B, Ib).

Urine Diagnostic Procedures

The gold standard for the diagnosis of UTI is the urine examination, including quantitative urine culture and its assessment, with appropriate clinical examinations and typical symptom assessment (V).

Urine Dipsticks In patients with a low pretest probability, a negative

test for nitrite/leukocytes may be considered to rule out UTI with sufficient certainty (IIa). The detection of blood, leukocytes, and nitrite independently increases the likeli- hood of the presence of a UTI. The combination of the positive findings further increases the likelihood of the diagnosis (Ib).

Urine Microscopy With urine microscopy, it may be considered that

UTIs can be largely ruled out, if the investigator has ad- equate experience (Ia). The centrifugation of the urine for the microscopic detection of bacteria does not lead to a greater accuracy of the diagnosis (Ib). It may be consid- ered, that if leukocytes are missing at urine microscopy, a UTI can be excluded (IIIb).

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Urine Culture

In patients with typical symptoms, colony counts of up to 10.3–10.4 CFU/mL of typical uropathogens can al- ready be clinically relevant for clinical symptoms (Table 3) if they were detected in mono cultures (i.e., only one type of bacteria) of typical uropathogens (V).

Urine samples for cultural microbiological diagnos- tics need to be processed immediately. If the sample can- not be processed immediately, the urine needs to be stored at 2°–8  ° C until further examination (V). Quanti- tative urine culture with species identification and sus- ceptibility testing is an indispensable prerequisite for tar- geted therapy, especially in pyelonephritis and recurrent UTIs (V).

Flow Cytometry

Urine flow cytometry is a laboratory-based method to standardize urine sediment analysis. The automated an- alyzers are capable to quantify for examples white blood counts (WBC) or bacteria. While clinical performance with a sensitivity (specificity) of 0.87 (0.67) for WBCs and 0.92 (0.60) for bacteria seems promising, a system- atic review and meta-analysis concluded that due to methodological shortcomings further studies are needed [14].

Imaging Diagnostics and Endoscopy For the diagnosis of acute pyelonephritis in healthy

women without complicating factors, further diagnostic procedures are recommended to rule out complicating factors (e.g., sonography; V). In women without recur- rent UTI and without relevant comorbidities, routine cystoscopy ought not to be performed (B, IIb).

Differential Diagnosis – Diagnostic Strategies In the case of non-specific symptoms, or inconsistent

urine examination, including negative urine culture, oth- er diagnoses, such as gynecological infections, like chla- mydia or trichomonas infection, should be considered at an early stage (V).

Bacterial Spectrum The most common cause of uncomplicated UTIs is E.

coli, followed by Staphylococcus saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis. Other pathogens are rare (Ia). Enterococci are most commonly found in mixed infections. Therefore, their pathogenicity is uncertain in uncomplicated UTIs (Ic).

Figure 2 shows the clinical microbiological pathway for diagnosis and therapy of symptomatic patients.

Key Messages

Uncomplicated UTIs are responsible for a large pro- portion of all antibiotic prescriptions and pathogen resis- tance is increasing worldwide. This is a major challenge in health care and therefore requires a responsible and restricted handling of antibiotic prescriptions across all health care professions.

Patient-reported symptom assessment is a key in the diagnostic evaluation of acute cystitis. The validated ACSS is an accurate tool for the diagnosis of acute un- complicated cystitis in women. It may be considered in the patient follow-up for clinical outcome assessment and in the determination of the effect of therapy.

The performance of a differential diagnosis is impor- tant in cases of non-specific symptoms, or inconsistent urine examination, including negative urine culture, and other diagnoses, such as gynecological infections with chlamydia or trichomonas, should be considered at an early stage of patient examination.

The most common cause of uncomplicated UTIs is E. coli, followed by Staphylococcus saprophyticus, Klebsiella pneumoniae, and Proteus mirabilis. Other pathogens are rare. Urine analysis, including microbiology, is the gold

Table 3. Cut-off values (colony forming units [CFU]/mL) for the diagnosis of different urinary tract infections and asymptomatic bacteriuria [15]

Diagnosis Evidence of bacteria, CFU/mL

Urine collection

Acute uncomplicated cystitis in women

103 Midstream urine

Acute uncomplicated pyelonephritis

104 Midstream urine

Asymptomatic bacteria 105 In women: evidence in 2 consecutively midstream urine samples. In men: evidence in 1 midstream urine sample. For catheter urine: 102 CFU/mL

Clinical Practice Guideline: Uncomplicated UTIs

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Symptomatic patient: dysuria,

alguria, pollakisuria, leukozcturia, fever,

flank pain

Uncomplicated cystitis of women

with low risk

Other patients, for example, infection of the upper urinary tract

or complicated urinary tract infection

Urine culture with antibiogram and empiric therapy or

Targeted therapy after availability of antibiogram

Patient with special indication,

for example, pregnancy or intervention in the

urinary tract

Clinical decision: definitive case for

therapy

Nitrite positive urine?

Leukozcte positive urine?

Reevaluation of the clinical symptoms Options according to individual decision: 1. Watchful waiting with/without symptomatic therapy 2. Empiric antibiotic therapy 3. Further evaluation, for example, with gynecological, nephrological or urological work up

No screening for asymptomatic bacteriuria

Urine culture with antibiogram, targeted therapy after

availability of antibiogram

Empiric therapy

culture with antibiogram only if increase in local resistance

pattern to standard antibiotics

No

No

No

No, not sure

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Fig. 2. Clinical microbiological pathway for diagnosis and therapy of symptomatic patients. Adapted from the guideline version [6].

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standard for the diagnosis of UTI, including quantitative urine culture, with appropriate clinical examinations and typical symptom assessment. Nevertheless, performing urine culture in every patient is economically not feasible; therefore, in women who have no risk factors for compli- cated UTIs, complain of typical symptoms (e.g., pain on micturition, frequent urination, urgency), have no vagi- nal symptoms (itching, altered discharge), have no fever, and no flank pain, the presence of an uncomplicated cys- titis may be considered with high probability.

In patients with persistent hematuria or persistent detection of pathogens other than E. coli, further stud- ies such as urethrocystoscopy and further imaging ought to be performed. In patients with recurrent UTIs, a urine culture and a single sonography should be per- formed.

Disclosure Statement

S. Schmidt and J. Kranz: Received third party funds from Leo Pharma.

L. Schneidewind: Received third party funds from Astellas, Monika Kutzner Stiftung.

C. Lebert: Received financial fees from Pfizer. K. Naber: Advisory board member of Accovion, Basilea, Bion-

orica, Cubist, Enteris, Galenus, Helperby, Leo Pharma, Merlion, OM Pharma, Paratek, Pierre Fabre, Rosen Pharma, Zambon. Re- ceived financial fees from Bionorica, Daiichi Sanchyo, Leo Phar- ma, MerLion, OM-Pharma, Rosen Pharma, Zambon. Received third party funds from Basilea, Bionorica, Enteris, Helperby, Mer- lion, OM-Pharma, Rosen-Pharma, Zambon.

W. Vahlensieck: Advisory board member of Bene, Bionorica, Fresenius, Omega/Abtei, Pfizer, Repha. Received financial fees from Akademie der Deutschen Urologen, Bionorica, CGC Cra- mer, Fischerappelt, Fresenius, Gilead, Infectopharm, MDS, MedConcept, MIM-Verlag, Omega/Abtei, Pfleger, Springer-Ver- lag, Strathmann Thieme-Verlag, Uromed.

F. Wagenlehner: Advisory board member of Achaogen, Astel- las, AstraZeneca, Bionorica, Cubist, Galenus, Leo Pharma, Mer- Lion, MSD, OM-Pharma, Pierre Fabre, Pierelle Research, Pfizer, Rosen Pharma, Zambon. Received financial fees from Achaogen, Astellas, AstraZeneca, Bionorica, Cubist, Galenus, Leo Pharma, MerLion, MSD, OM-Pharma, Pierre Fabre, Pierelle Research, Pfiz- er, Rosen Pharma, Zambon. Received third party funds from As- tellas, AstraZeneca, Bionorica, Calixa, Cubist, DFG, Europ. Ass. f. Urologie, Galenus, Hess. Minist. f. Wirtschaft und Kunst, Merlion, MSD, OM-Pharma, Rosen Pharma, Zambon.

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