Clinical Practice Guideline
Uncomplicated Bacterial Community- acquired Urinary Tract Infection in Adults
Epidemiology, Diagnosis, Treatment, and Prevention
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Background: Uncomplicated bacterial community-acquired urinary tract infection is among the more common infections in outpatient practice. The resistance level of pathogens has risen markedly. This S3 guideline contains recommendations based on current evidence for the rational use of antimicrobial agents and for the prevention of inappropriate use of certain classes of antibiotics and thus of the resulting drug resistance. The prevention of recurrent urinary tract infection is considered in this guideline for the first time.
Methods: The guideline was updated under the aegis of the German Urological Society (Deutsche Gesellschaft für Urologie). A systematic literature search (period: 2008–2015) concerning the diagnosis, treatment, and prevention of uncomplicated urinary tract infections was carried out in the Cochrane Library, MEDLINE, and Embase databases. Randomized, controlled trials and systemic reviews were included. Relevant guidelines were identified in a guideline synopsis.
Results: Symptom-oriented diagnostic evaluation is highly valued. For the treatment of cystitis, fosfomycin-trometamol, nitrofurantoin, nitroxolin, pivmecillinam and trimethoprim are all equally recommended. Fluorquinolones and cephalosporins are not recommended. Uncomplicated pyelonephritis with a mild to moderate clinical course ought to be treated with oral cefpodoxime, ceftibuten, ciprofloxacin, or levofloxacin. For acute, uncomplicated cystitis, with mild to moderate symptoms, symptomatic treatment alone may be considered instead of antibiotics after discussion of the options with the patient. Mainly non-antibiotic measures are recommended for prophylaxis against recurrent urinary tract infection.
Conclusion: Physicians who treat uncomplicated urinary tract infections should familiarize themselves with the newly revised guideline’s recommendations on the selection and dosage of antibiotic treatment so that they can responsibly evaluate and plan antibiotic treatment for their affected patients.
Uncomplicated bacterial urinary tract infection is one of the most commonly occurring community-acquired infections. In 2013, 7.32% of the female members of the German health insurance fund Barmer GEK were diagnosed with uncomplicated urinary tract infection (uUTI; ICD-10 code N39.0), 1.73% with acute uncomplicated cystitis (AUC; N30.0), and 0.16% with acute uncomplicated pyelonephritis (AUP: N10) (1). The estimated incidence of UTI in women over 18 years of age in the USA is 12.6% (2). On the basis of the Barmer GEK data, German prescription practice for diagnosed cystitis runs contrary to the recommendations of the guideline issued in 2010. For example, the drug class most commonly prescribed for the treatment of UTI in 2012 was a fluoroquinolone, given in 48% of cases (1). Antibiotic resistance is a growing global problem that is leading to considerably increased costs and daunting challenges in health care (1, 3–5). According to the data of the ARMIN resistance-monitoring project in the German federal state of Lower Saxony, for instance, resistance of Escherichia coli to ciprofloxacin has increased from 10.3% to 14.7% in the past 10 years (6). Growing resistance to cotrimoxazole and ampicillin has also been noted (7, 8). It is known that different antibiotics exert a varying amount of selection pressure not only on the pathogens responsible for the infection, but also on the uninvolved local flora. This is termed collateral damage, and the substances used in the treatment of uncomplicated UTI with the greatest effect in this respect are the cephalosporins and fluoroquinolones.
The goal of updating the guideline is to provide clinical practice recommendations for the diagnosis, treatment, and prevention of uncomplicated bacterial community-acquired UTI in adults. The recommendations and statements are intended to help members of all professions concerned with the diagnosis, treatment, and prophylaxis of acute uUTI: primary-care physicians, gynecologists, infectious disease specialists, internists working in primary care, clinical pathologists, microbiologists, urologists, and pharmacists.
The revised S3 guideline was compiled according to the regulations of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) (9) under the aegis of the German Urology Society (Deutsche Gesellschaft für Urologie, DGU). It was decided not to solicit or accept funding from the pharmaceutical industry. All authors’ conflicts of interests were publicized. The content of the central statements and recommendations was voted on separately by experts with and without conflicts of interest. A complete list of the authors of the updated S3 guideline and the professional societies they represent is provided in the eBox.
For the first time, the guideline was supported by UroEvidence@Deutsche Gesellschaft für Urologie, the knowledge transfer center of the DGU. UroEvidence was responsible for sifting of the identified publications by two experts working independently (JK, SS), literature management (JK, SS), and assessment of the level of evidence and risk of bias in the treatment studies (JK, SS, LS). Evidence assessment was based on the results of a systematic survey of the literature on the topics diagnosis and treatment of uUTI and prevention of recurring UTI (rUTI). Details of the search strategy can be found (in German) in the long version of the guideline (10). The databases Cochrane Library, MEDLINE, and Embase were searched for publications in the period 1 January 2008 (continuing from the systematic survey carried out for the first edition of the guideline published in 2010) to 31 December 2015. Furthermore, the data of all currently available relevant studies were incorporated in the interests of a “living guideline.” The publications identified by the literature search were sorted according to topic and divided accordingly among the working groups. To be included, studies not only had to have a patient population as defined below, but also had to fulfill the requirements for study design: randomized controlled trial (RCT) or systematic review with or without meta-analysis. A flow chart of the literature survey according to the PRISMA statement (11) is shown in eFigure 1. The risk of bias was assessed for all studies included: for RCTs using the Cochrane Risk of Bias Tool, for systematic reviews and meta-analyses using the Scottish Intercollegiate Guideline Network (SIGN) system (12, 13). Assessment of the level of evidence followed the 2009 criteria of the Oxford Centre for Evidence-based Medicine (14). The evidence tables (effect sizes) of the recommended antibiotics are shown in eTable 1.
A guideline synopsis was carried out to identify existing relevant guidelines. The guidelines selected for inclusion (n = 19) were evaluated independently by two authors of the present guideline according to the AGREE criteria (15).
The recommendation grades were decided by the members of the guideline group (see classification in eFigure 2). Evidence-based statements and recommendations were formulated over the course of 17 consensus/telephone conferences. Formal consensus finding took the form of a nominal group process under the leadership of an external moderator from the AWMF (Prof. Kopp). The version of the guideline for consultation was published via the professional societies and on the homepage of the AWMF (10). Comments were discussed by the guideline group and taken into consideration in the final version. The methods, the comments made during the consultation process, and the steps taken to determine conflicts of interest are described in detail in the guideline report (10).
The different categories of patients with uUTI ought to be considered separately for purposes of diagnosis, treatment, and prevention:
- Non-pregnant women in the premenopause with no relevant comorbidity (standard group)
- Pregnant women with no relevant comorbidity
- Women in the postmenopause with no relevant comorbidity
- Young men with no relevant comorbidity
- Patients with diabetes mellitus and stable metabolism with no relevant comorbidity
On the basis of the systematic literature survey, 75 recommendations and 68 statements were agreed upon without discord both by participants with and those without conflicts of interest. The definitions can be found in the Box.
In the following, we present selected recommendations on diagnosis (eTable 2, eFigures 3 and 4), treatment (Table 1, Table 2, eFigure 4), and prevention (Table 3) for the largest groups of patients (nonpregnant women in the premenopause and pregnant women with no relevant comorbidity). For the other groups of patients defined above, the reader is referred to the long version of the guideline (10).
The diagnostic techniques are intended to establish whether a UTI is present and, in some cases, to identify the pathogen responsible for the infection and to determine how it can be treated.
Confirmation of acute uncomplicated cystitis (AUC) on clinical criteria alone is afflicted by an error rate of up to one third (16, 17). The only way of reducing diagnostic inaccuracy would be always to perform a urine culture with determination of all pathogens, even those present in low counts (gold standard). However, pursuing this maximal strategy in nonselected patients is neither economically reasonable (18) nor practicable in daily routine, because the delay before the results of a urine culture are known means that they would have no essential influence on the empirical short-term treatment.
Diagnosis in the standard group: nonpregnant women in the premenopause
Acute uncomplicated cystitis (AUC)—There is a probability of almost 80% that women who have no risk factors for complicated UTI, complain of typical symptoms (pain on passing water, pollakisuria, severe urgency), have no vaginal symptoms (itchiness, altered secretions), and deny fever and flank pain will have AUC (e1, e2) (evidence level IIa). A urine culture is unnecessary in women with clear-cut clinical symptoms of uncomplicated, nonrecurrent or non-treatment-resistant cystitis. In a first manifestation of AUC, or if the patient is unknown to the physician, the medical history ought to be taken and a symptom-related medical examination carried out (evidence level V-B). With the validated Acute Cystitis Symptom Score (ACSS) questionnaire (eFigure 5), AUC can be diagnosed with a high degree of certainty based on clinical criteria (94.7% sensitivity and 82.4% specificity with a total score of ≥ 6 points), the severity of the symptoms can be estimated, the patient’s progress can be followed, and the treatment effect is rendered measurable (evidence level IIb) (19, 20).
Acute uncomplicated pyelonephritis (AUP)—In addition to establishing the patient’s general medical history, physical examination and urinalysis including urine culture should be carried out (evidence level V-A). Moreover, further investigations (e.g., sonography) should be considered with the goal of excluding complicating factors (evidence level V-A) (e3).
Recurring urinary tract infection (rUTI)—In patients with rUTI, urine ought to be cultured and sonography ought to be performed once only. No other invasive diagnostic tests ought to be carried out (evidence level Ib-B) (e7, e8). In patients with persisting hematuria or persisting presence of pathogens other than E. coli, urethrocystoscopy and further imaging are recommended (evidence level V-B) (e2, e9, e10).
Diagnosis in pregnant women without relevant comorbidity
Acute uncomplicated cystitis (AUC)—The patient’s medical history ought to be taken just as in nonpregnant patients, but physical examination and urinalysis including urine culture are strongly recommended (evidence level V-A). Following the antibiotic treatment of AUC in pregnancy, eradication of the pathogen should be verified by urine culture (evidence level V-A).
Acute uncomplicated pyelonephritis (AUP)—The diagnosis of AUP in pregnant women is analogous to that in nonpregnant patients (evidence level V). Physical examination and urinalysis including urine culture are mandatory (evidence level V-A). If pyelonephritis is suspected, sonography of the kidneys and urinary tract should be carried out (evidence level V-A) (e11, e12). Following the antibiotic treatment of pyelonephritis in pregnancy, eradication of the pathogen should be verified by urine culture (evidence level V-A).
Asymptomatic bacteriuria (ASB)—Systematic screening for ASB ought not to be carried out in pregnant women (EG Ib-B) (21, e13–e18). The strip tests generally used for this purpose have low sensitivity (14 to 50%) for ASB in pregnancy (21–23).
Recurring urinary tract infection (rUTI)—The diagnostic work-up in pregnant women without relevant comorbidity broadly corresponds to that in young women with no relevant comorbidity.
An overview of the reference values for the diagnosis of various UTIs and ASB can be found in eTable 2.
The following criteria should be taken into account when deciding which antibiotic to use (evidence level Ia-A):
- The patient’s individual risk
- The spectrum of pathogens and antibiotic sensitivity
- The efficacy of the antimicrobial substance
- The adverse drug reactions
- The effects on the resistance situation in the individual patient (collateral damage) and/or the general population (epidemiological effects)
Acute uncomplicated cystitis: standard group
The spontaneous recovery rate in AUC is high (at 1 week: clinically 28%, clinically and microbiologically 37%). The central goal of treatment is swift relief of the clinical symptoms, i.e., within a matter of days (24). The small number of placebo-controlled studies performed have shown that the symptoms resolve more rapidly with antibiotic treatment than with placebo (25). In a recent study, Gágyor et al. compared the effect of primarily symptomatic ibuprofen treatment with that of immediate administration of an antibiotic. Around two thirds of patients with purely symptomatic treatment needed no further antibiotic (26). In light of these findings, nonantibiotic, symptomatic treatment may be considered in cases of AUC with mild or moderate symptoms (evidence level IA-B). Due consideration should be paid to the patients’ preferences when deciding what course of treatment to follow. This is especially true for primarily nonantibiotic treatment, which may be associated with a greater burden of symptoms (freedom from symptoms after 7 days: ibuprofen 163/232 patients versus fosfomycin 186/227 patients, 95% confidence interval [−19.4; −4.0]) (26). The decision should be made together with the patient.
The presence of ASB increases the risk of infection for patients undergoing urinary tract interventions in which mucosal trauma can be anticipated. For this reason ASB should be actively sought in such cases, and if found it should be treated (evidence level IA-A) (27).
The evidence from randomized studies in this respect is primarily for transurethral resection of the prostate. There is no evidence regarding low-risk interventions, e.g., urethrocystocopy.
Kazemier et al. showed that in women with low risk pregnancy and ASB the risk of symptomatic cystitis increased from 7.9% to 20.2% if they were treated with placebo or not at all (for pyelonephritis from 0.6% to 2.4%) (28). However, ASB did not increase the risk of premature birth for nontreated patients in this low risk pregnancy population (28).
General comment on antibiotic treatment of acute uncomplicated cystitis
Among the group of antibiotics or classes of antibiotic drugs that are basically suitable for the treatment of AUC—aminopenicillins in combination with a betalactamase inhibitor, group 2 and 3 cephalosporins, fluoroquinolones, fosfomycin-trometamol, nitrofurantoin, nitroxolin, pivmecillinam, trimethoprim or cotrimoxazole—the fluoroquinolones and cephalosporins are associated with the greatest risk of microbiological collateral damage in the form of selection of multiresistant pathogens and development of Clostridium difficile-associated colitis (29).
Since fluoroquinolones and cephalosporins have an important role in complicated infections, the clinical consequences of increased resistance by using them in uncomplicated infections was rated as more severe than for other antibiotics recommended for the treatment of AUC. (evidence level V). It is thus strongly recommended that the fluoroquinolones and cephalosporins are not used in the treatment of AUC unless there is a contraindication for alternative substances (evidence level V-A) (Table 1). In addition, patient-relevant clinical endpoints (clinical improvement of symptoms, recurrences, ascending infections) and the individual risk (e.g., Achilles tendon rupture with the fluoroquinolones) should be taken into account.
Acute uncomplicated pyelonephritis: standard group
Patients with AUP should receive efficacious antibiotic treatment as soon as possible, because kidney damage (30), though not frequent, is more likely with increasing duration, severity, and frequency of such infections. In choosing the best antibiotic, the eradication rates, sensitivity, collateral damage, and special characteristics with regard to adverse drug reactions should be taken into account (evidence level V) (Table 2, eFigure 4). Because the prevalence is much lower than that of AUC (0.16%) (1), less heed has to be paid to collateral damage (1).
Prevention of recurring urinary tract infection: standard group
Before initiation of long-term prophylactic drug treatment, a woman with rUTI should be counseled in detail on avoidance of risks (e.g., not drinking enough, overcooling, excessive intimate hygiene) (evidence level Ib-A) (e19, e20). If appropriate preventive measures have been taken but rUTI persists, long-term antibiotic prophylaxis ought to be preceded by oral administration of an E. coli lysate (OM-89) for 3 months (evidence level Ia-B) (e21). Immunoprophylaxis by means of three parenteral injections of inactivated specified enterobacteria at 1-week intervals may be considered (evidence level Ib-C) (28). Moreover, mannose may be considered (e22); alternatively, various phytotherapeutic agents may be considered (evidence level Ib-C) (e23, e24). If the patient’s level of suffering is high, failure of behavioral modification and nonantibiotic prophylaxis ough to be followed by continual long-term antibiotic prophylaxis for 3 to 6 months (evidence level IV-B) (31) (Table 3). In the presence of an association with sexual intercourse, postcoital prophylaxis with a single dose ought to be used instead of long-term administration of antibiotics (evidence level Ib-B) (31, e25, e26).
The high frequency of uncomplicated bacterial community-acquired urinary tract infections in adults and their treatment with antibiotics exerts massive antibiotic selection pressure on the bacteria involved and also on the collateral flora, resulting in significant influence on the selection of antibiotic-resistant bacteria in the population. Careful use of antibiotics for this indication is therefore extremely important in safeguarding the efficacy of antibiotic treatment. The treatment recommendations were thus crucially influenced by considerations of antibiotic stewardship. The evidence- and consensus-based recommendations of the updated S3 guideline therefore need to be widely implemented by all categories of medical professionals entrusted with the treatment of urinary tract infections in order to improve the standards of care and ensure a forward-looking policy on the use of antibiotics.
International reviewer: Gernot Bonkat (Switzerland)
Coordination and external moderation: Ina Kopp, AWMF Institute for Medical Knowledge Management, University of Marburg
We are especially grateful to Alexandra Pulst, scientific assistant at the Department of Care Research, Institute for Public Health and Nursing Care Research, University of Bremen for her support in compiling the guideline synopsis and evidence assessment.
Conflict of interest statement
Prof. Wagenlehner has received consultancy fees from Achaogen, Astra Zeneca, Bionorica, MSD, Pfizer, Rosen Pharma, Vifor Pharma, and Leo Pharma. Furthermore, he has received funds to conduct clinical studies from MSD, Pfizer, Vifor Pharma, Rosen Pharma, and Leo Pharma.
Dr. Kranz has received funds to carry out a systematic review from Leo Pharma.
Dr. Schmidt has received funds to carry out a systematic review from Leo Pharma.
The remaining authors declare that no conflict of interest exists.
Manuscript submitted on 30 August 2017, revised version accepted on
25 October 2017
Translated from the original German by David Roseveare
Dr. med. Jennifer Kranz, FEBU
Klinik für Urologie und Kinderurologie, St. Antonius-Hospital
Akademisches Lehrkrankenhaus der RWTH Aachen
52249 Eschweiler, Germany
For eReferences please refer to:
eFigures, eBox, eTables:
Department of Urology and Pediatric Urology, St. Antonius Hospital Eschweiler, Academic Teaching Hospital of RWTH Aachen, Eschweiler: Dr. Kranz
UroEvidence@Deutsche Gesellschaft für Urologie, Berlin: Dr. Kranz, Dr. Schmidt, Dr. Schneidewind
Pharmacy, Nuremberg Hospitals: Dr. Lebert
Hematology/Oncology, Department of Internal Medicine C, Faculty of Medicine, University of Greifswald: Dr. Schneidewind
Department of Care Research, Institute for Public Health and Nursing Care Research, University of Bremen: PD Dr. Schmiemann
Department of Urology, Pediatric Urology and Andrology, University Hospital of Gießen and Marburg Ltd., Justus-Liebig University Gießen: Prof. Wagenlehner
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