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

Uncomplicated, bacterial, community-acquired urinary tract infections (UTIs), including cystitis and pyelonephritis, are among the most common infections in the outpatient setting. Data on antibiotic consumption in uncomplicated UTIs from the German Barmer health insurance, one of the largest health insurance funds, on prescribing 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 fluoroquinolones (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 significantly increased in recent years. Recognition of this fact has led to an international re-evaluation of therapeutic recommendations in uncomplicated UTIs [4]. In accordance with this global initiative and the achievements in the antibiotic 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 guideline classification form, where S3 represents the highest methodological standard and involves both evidence- and consensus-based concepts to achieve guideline recommendations from an interdisciplinary panel group [7].

The guideline recommendations address all medical specialties involved in the diagnostics, therapy, management, and prevention of acute uncomplicated UTIs (Table 1), for example, general practitioners, gynecologists, infectious disease specialists, microbiologists, nephrologists, urologists, and laboratory physicians.

Here, we present the main content of the updated guideline in 2 parts. Part I focuses on the recommendations 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 pyelonephritis and prophylaxis of recurrent UTIs.

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

The AWMF S3 clinical guideline is based on an interdisciplinary 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 literature published between January 2010 and December 2015. International clinical guidelines, systematic reviews, meta-analysis, and randomized clinical trials on this topic were considered for inclusion. 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 publications, 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 recommendations 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.

A UTI is classified as uncomplicated if there are no relevant functional or anatomical anomalies in the urinary tract, no relevant renal functional impairment and 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 micturition (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 bacteriuria. The term ‘asymptomatic UTI’ ought not to be used.

• Recurrent uncomplicated UTIs: A recurrent UTI is assumed if relapse rates of ≥2 symptomatic episodes occur within 6 months or ≥3 symptomatic episodes within 12 months.

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.

Diagnostic methods are designed to detect the presence 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).

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 diagnosis 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 esterase alone or in combination) further increases the likelihood of a UTI (Ia). Diagnosis without direct patient contact 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, 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 investigated in Germany. Experiences with telemedicine from other countries cannot directly be transferred to the German healthcare system (Ib).

In the following, specific recommendations for the diagnosis in non-pregnant premenopausal women without other relevant concomitant diseases are presented (standard 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).

If women who have no risk factors for complicated UTIs complain of typical symptoms (pain on micturition, pollakisuria, urgency), have no vaginal symptoms (itching, altered discharge), have no fever and no flank pain, the presence of an uncomplicated cystitis may be considered with high probability (IIa).

In the first manifestation of an acute UTI or, if the patient is unknown to the doctor, a symptom-related medical examination with clinical examination ought to be performed (B, V). The diagnosis of uncomplicated cystitis 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 follow the course of cystitis over time and the effect of therapy (IIb) [13]. The ACSS questionnaire is translated and validated in several languages (www.acss.world).

In women with uncomplicated, non-recurrent or -refractory cystitis, with clear clinical symptoms, no microbiological examination is recommended (IIIc). In symptomatic women, the detection of Escherichia coli in the midstream urine, independent of the number of pathogens, is predictive for a bacterial UTI. In contrast, the detection of Enterococci and group B Streptococci in the midstream urine is not predictive for a UTI (Ib).

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

In non-pregnant women without other relevant concomitant diseases, screening for asymptomatic bacteriuria ought not to be carried out (A, Ia).

In patients with persistent hematuria or persistent detection 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 performed. Further invasive diagnostics ought not to be performed (B, Ib).

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).

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 likelihood of the presence of a UTI. The combination of the positive findings further increases the likelihood of the diagnosis (Ib).

With urine microscopy, it may be considered that UTIs can be largely ruled out, if the investigator has adequate 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 considered, that if leukocytes are missing at urine microscopy, a UTI can be excluded (IIIb).

In patients with typical symptoms, colony counts of up to 10.3–10.4 CFU/mL of typical uropathogens can already 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 diagnostics need to be processed immediately. If the sample cannot be processed immediately, the urine needs to be stored at 2°–8°C until further examination (V). Quantitative urine culture with species identification and susceptibility testing is an indispensable prerequisite for targeted therapy, especially in pyelonephritis and recurrent UTIs (V).

Urine flow cytometry is a laboratory-based method to standardize urine sediment analysis. The automated analyzers 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 systematic review and meta-analysis concluded that due to methodological shortcomings further studies are needed [14].

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 recurrent UTI and without relevant comorbidities, routine cystoscopy ought not to be performed (B, IIb).

In the case of non-specific symptoms, or inconsistent urine examination, including negative urine culture, other diagnoses, such as gynecological infections, like chlamydia or trichomonas infection, should be considered at an early stage (V).

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.

Uncomplicated UTIs are responsible for a large proportion of all antibiotic prescriptions and pathogen resistance 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 uncomplicated 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 important 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 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 complicated UTIs, complain of typical symptoms (e.g., pain on micturition, frequent urination, urgency), have no vaginal symptoms (itching, altered discharge), have no fever, and no flank pain, the presence of an uncomplicated cystitis may be considered with high probability.

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

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, Bionorica, Cubist, Enteris, Galenus, Helperby, Leo Pharma, Merlion, OM Pharma, Paratek, Pierre Fabre, Rosen Pharma, Zambon. Received financial fees from Bionorica, Daiichi Sanchyo, Leo Pharma, MerLion, OM-Pharma, Rosen Pharma, Zambon. Received third party funds from Basilea, Bionorica, Enteris, Helperby, Merlion, 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 Cramer, Fischerappelt, Fresenius, Gilead, Infectopharm, MDS, MedConcept, MIM-Verlag, Omega/Abtei, Pfleger, Springer-Verlag, Strathmann Thieme-Verlag, Uromed.

F. Wagenlehner: Advisory board member of Achaogen, Astellas, AstraZeneca, Bionorica, Cubist, Galenus, Leo Pharma, MerLion, 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, Pfizer, Rosen Pharma, Zambon. Received third party funds from Astellas, AstraZeneca, Bionorica, Calixa, Cubist, DFG, Europ. Ass. f. Urologie, Galenus, Hess. Minist. f. Wirtschaft und Kunst, Merlion, MSD, OM-Pharma, Rosen Pharma, Zambon.

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